Quinoline derivatives as antibacterial agents

ABSTRACT

Use of a compound for the manufacture of a medicament for the treatment of a bacterial infection provided that the bacterial infection is other than a Mycobacterial infection, said compound being a compound of Formula (Ia) or (Ib) 
                         
a pharmaceutically acceptable acid or base addition salt thereof, a quaternary amine thereof, a stereochemically isomeric form thereof, a tautomeric form thereof or a N-oxide form thereof, wherein R 1  is hydrogen, halo, haloalkyl, cyano, hydroxy, Ar, Het, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di(Ar)alkyl; p is 1, 2 or 3; R 2  is hydrogen; alkyl; hydroxy; mercapto; optionally substituted alkyloxy; alkyloxyalkyloxy; alkylthio; mono or di(alkyl)amino wherein alkyl may optionally be substituted; Ar; Het or a radical of formula
 
                         
R 3  is alkyl, Ar, Ar-alkyl, Het or Het-alkyl; q is zero, 1, 2, 3 or 4; X is a direct bond or CH 2 ; R 4  and R 5  each independently are hydrogen, alkyl or benzyl; or R 4  and R 5  may be taken together including the N to which they are attached; R 6  is hydrogen or a radical of formula
 
                         
R 7  is hydrogen, alkyl, Ar or Het; R 8  is hydrogen or alkyl; R 9  is oxo; or R 8  and R 9  together form the radical —CH═CH—N═; and R 11  is as defined in the claims.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a national stage application of Patent ApplicationNo. PCT/EP2006/064847, filed Jul. 31, 2006, which in turn claims thebenefit of EPO Patent Application No. 05107155.3, filed Aug. 3, 2005.The complete disclosures of the aforementioned related patentapplications are hereby incorporated herein by reference for allpurposes.

The present invention relates to the use of quinoline derivatives forthe manufacture of a medicament for the treatment of a bacterialinfection.

Resistance to first-line antibiotic agents is an emerging problem. Someimportant examples include penicillin-resistant Streptococcuspneumoniae, vancomycin-resistant enterococci, methicillin-resistantStaphylococcus aureus, multi-resistant salmonellae.

The consequences of resistance to antibiotic agents are severe.Infections caused by resistant microbes fail to respond to treatment,resulting in prolonged illness and greater risk of death. Treatmentfailures also lead to longer periods of infectivity, which increase thenumbers of infected people moving in the community and thus exposing thegeneral population to the risk of contracting a resistant straininfection. Hospitals are a critical component of the antimicrobialresistance problem worldwide. The combination of highly susceptiblepatients, intensive and prolonged antimicrobial use, and cross-infectionhas resulted in infections with highly resistant bacterial pathogens.

Self-medication with antimicrobials is another major factor contributingto resistance. Self-medicated antimicrobials may be unnecessary, areoften inadequately dosed, or may not contain adequate amounts of activedrug.

Patient compliance with recommended treatment is another major problem.Patients forget to take medication, interrupt their treatment when theybegin to feel better, or may be unable to afford a full course, therebycreating an ideal environment for microbes to adapt rather than bekilled.

Because of the emerging resistance to multiple antibiotics, physiciansare confronted with infections for which there is no effective therapy.The morbidity, mortality, and financial costs of such infections imposean increasing burden for health care systems worldwide.

Therefore, there is a high need for new compounds to treat bacterialinfections, especially for the treatment of infections caused byresistant strains.

Substituted quinolines were already disclosed in U.S. Pat. No. 5,965,572(The United States of America) for treating antibiotic resistantinfections and in WO 00/34265 to inhibit the growth of bacterialmicroorganisms.

WO 2004/011436, WO2005/070924, WO2005/070430 and WO2005/075428 disclosesubstituted quinoline derivatives having activity against Mycobacteria,in particular against Mycobacterium tuberculosis. One particularcompound of these substituted quinoline derivatives is described inScience (2005), 307, 223-227.

None of these publications disclose the use of the present substitutedquinoline derivatives according to this invention.

SUMMARY OF THE INVENTION

The present invention relates to the use of a compound for themanufacture of a medicament for the treatment of a bacterial infection,said compound being a compound of Formula (Ia) and (Ib)

a pharmaceutically acceptable acid or base addition salt thereof, aquaternary amine thereof, a stereochemically isomeric form thereof, atautomeric form thereof or a N-oxide form thereof, wherein

-   R¹ is hydrogen, halo, haloalkyl, cyano, hydroxy, Ar, Het, alkyl,    alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or    di(Ar)alkyl;-   p is an integer equal to 1, 2 or 3;-   R² is hydrogen; alkyl; hydroxy; mercapto; alkyloxy optionally    substituted with amino or mono or di(alkyl)amino or a radical of    formula

wherein Z is CH₂, CH—R¹⁰, O, S, N—R¹⁰ and t is an integer equal to 1 or2 and the dotted line represents an optional bond; alkyloxyalkyloxy;alkylthio; mono or di(alkyl)amino wherein alkyl may optionally besubstituted with one or two substituents each independently be selectedfrom alkyloxy or Ar or Het or morpholinyl or 2-oxopyrrolidinyl; Ar; Hetor a radical of formula

wherein Z is CH₂, CH—R¹⁰, O, S, N—R¹⁰; t is an integer equal to 1 or 2;and the dotted line represents an optional bond;

-   R³ is alkyl, Ar, Ar-alkyl, Het or Het-alkyl;-   q is an integer equal to zero, 1, 2, 3 or 4;-   X is a direct bond or CH₂;-   R⁴ and R⁵ each independently are hydrogen, alkyl or benzyl; or-   R⁴ and R⁵ together and including the N to which they are attached    may form a radical selected from the group of pyrrolidinyl,    2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, pyrazolidinyl, 2-imidazolinyl,    2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl,    pyridinyl, piperazinyl, imidazolidinyl, pyridazinyl, pyrimidinyl,    pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl, each of said    rings optionally being substituted with alkyl, halo, haloalkyl,    hydroxy, alkyloxy, amino, mono- or dialkylamino, alkylthio,    alkyloxyalkyl, alkylthioalkyl or pyrimidinyl;-   R⁶ is hydrogen or a radical of formula

wherein s is an integer equal to zero, 1, 2, 3 or 4; r is an integerequal to 1, 2, 3, 4 or 5; and R¹¹ is hydrogen, halo, haloalkyl, hydroxy,Ar, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkylor di(Ar)alkyl; or two vicinal R¹¹ radicals may be taken together toform together with the phenyl ring to which they are attached anaphthyl;

-   R⁷ is hydrogen, alkyl, Ar or Het;-   R⁸ is hydrogen or alkyl;-   R⁹ is oxo; or-   R⁸ and R⁹ together form the radical —CH═CH—N═;-   R¹⁰ is hydrogen, alkyl, hydroxyl, aminocarbonyl, mono- or    di(alkyl)aminocarbonyl, Ar, Het, alkyl substituted with one or two    Het, alkyl substituted with one or two Ar, Het-C(═O)—, Ar—C(═O)—;-   alkyl is a straight or branched saturated hydrocarbon radical having    from 1 to 6 carbon atoms; or is a cyclic saturated hydrocarbon    radical having from 3 to 6 carbon atoms; or is a cyclic saturated    hydrocarbon radical having from 3 to 6 carbon atoms attached to a    straight or branched saturated hydrocarbon radical having from 1 to    6 carbon atoms; wherein each carbon atom can be optionally    substituted with hydroxy, alkyloxy or oxo;-   Ar is a homocycle selected from the group of phenyl, naphthyl,    acenaphthyl, tetrahydronaphthyl, each optionally substituted with 1,    2 or 3 substituents, each substituent independently selected from    the group of hydroxy, halo, cyano, nitro, amino, mono- or    dialkylamino, alkyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl,    alkyloxycarbonyl, alkylcarbonyl, aminocarbonyl, morpholinyl and    mono- or dialkylaminocarbonyl;-   Het is a monocyclic heterocycle selected from the group of    N-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl, imidazolyl,    furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,    triazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a    bicyclic heterocycle selected from the group of quinolinyl,    isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, quinoxalinyl,    indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,    benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl,    2,3-dihydrobenzo[1,4]dioxinyl or benzo[1,3]dioxolyl; each monocyclic    and bicyclic heterocycle may optionally be substituted on a carbon    atom with 1, 2 or 3 substituents, each substituent independently    selected from the group of halo, hydroxy, alkyl or alkyloxy;-   halo is a substituent selected from the group of fluoro, chloro,    bromo and iodo and-   haloalkyl is a straight or branched saturated hydrocarbon radical    having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon    radical having from 3 to 6 carbon atoms or a cyclic saturated    hydrocarbon radical having from 3 to 6 carbon atoms attached to a    straight or branched saturated hydrocarbon radical having from 1 to    6 carbon atoms; wherein one or more carbon atoms are substituted    with one or more halo atoms;    provided that when R⁷ is hydrogen then the

radical may also be placed in position 4 of the quinoline ring; andprovided that the bacterial infection is other than a Mycobacterialinfection.

The present invention also relates to a method of treating a bacterialinfection provided that the bacterial infection is other than aMycobacterial infection, in a mammal, in particular a warm-bloodedmammal, more in particular a human, comprising administering aneffective amount of a compound of the invention to the mammal.

The compounds according to Formula (Ia) and (Ib) are interrelated inthat e.g. a compound according to Formula (Ib), with R⁸ equal to oxo isthe tautomeric equivalent of a compound according to Formula (Ia) withR² equal to hydroxy (keto-enol tautomerism).

DETAILED DESCRIPTION

In the framework of this application, alkyl is a straight or branchedsaturated hydrocarbon radical having from 1 to 6 carbon atoms; or is acyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms; oris a cyclic saturated hydrocarbon radical having from 3 to 6 carbonatoms attached to a straight or branched saturated hydrocarbon radicalhaving from 1 to 6 carbon atoms; wherein each carbon atom can beoptionally substituted with hydroxy, alkyloxy or oxo.

Preferably, alkyl is methyl, ethyl or cyclohexylmethyl.

An interesting embodiment of alkyl in all definitions used hereinbeforeor hereinafter is C₁₋₆alkyl which represents a straight or branchedsaturated hydrocarbon radical having from 1 to 6 carbon atoms such asfor example methyl, ethyl, propyl, 2-methyl-ethyl, pentyl, hexyl and thelike. A preferred subgroup of C₁₋₆alkyl is C₁₋₄alkyl which represents astraight or branched saturated hydrocarbon radical having from 1 to 4carbon atoms such as for example methyl, ethyl, propyl, 2-methyl-ethyland the like.

In the framework of this application, Ar is a homocycle selected fromthe group of phenyl, naphthyl, acenaphthyl, tetrahydronaphthyl, eachoptionally substituted with 1, 2 or 3 substituents, each substituentindependently selected from the group of hydroxy, halo, cyano, nitro,amino, mono- or dialkylamino, alkyl, haloalkyl, alkyloxy, haloalkyloxy,carboxyl, alkyloxycarbonyl, aminocarbonyl, morpholinyl and mono- ordialkylaminocarbonyl. Preferably, Ar is naphthyl or phenyl, eachoptionally substituted with 1 or 2 halo substituents.

In the framework of this application, Het is a monocyclic heterocycleselected from the group of N-phenoxypiperidinyl, piperidinyl, pyrrolyl,pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl andpyridazinyl; or a bicyclic heterocycle selected from the group ofquinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl,benzothienyl, 2,3-dihydrobenzo[1,4]dioxinyl or benzo[1,3]dioxolyl; eachmonocyclic and bicyclic heterocycle may optionally be substituted on acarbon atom with 1, 2 or 3 substituents, each substituent independentlyselected from the group of halo, hydroxy, alkyl or alkyloxy. Preferably,Het is thienyl or furanyl or pyridyl, most preferably Het is furanyl.

In the framework of this application, halo is a substituent selectedfrom the group of fluoro, chloro, bromo and iodo and haloalkyl is astraight or branched saturated hydrocarbon radical having from 1 to 6carbon atoms or a cyclic saturated hydrocarbon radical having from 3 to6 carbon atoms or a cyclic saturated hydrocarbon radical having from 3to 6 carbon atoms attached to a straight or branched saturatedhydrocarbon radical having from 1 to 6 carbon atoms; wherein one or morecarbon atoms are substituted with one or more halo atoms. Preferably,halo is bromo, fluoro or chloro and preferably, haloalkyl ispolyhaloC₁₋₆alkyl which is defined as mono- or polyhalosubstitutedC₁₋₆alkyl, for example, methyl with one or more fluoro atoms, forexample, difluoromethyl or trifluoromethyl, 1,1-difluoro-ethyl and thelike. In case more than one halo atom is attached to an alkyl groupwithin the definition of haloalkyl or polyhaloC₁₋₆alkyl, they may be thesame or different.

In the framework of this application, the quinoline ring of thecompounds of Formula (Ia) or (Ib) is numbered as follows:

The

radical may be placed on any available position of the quinoline moiety.

In the definition of Het, it is meant to include all the possibleisomeric forms of the heterocycles, for instance, pyrrolyl comprises1H-pyrrolyl and 2H-pyrrolyl.

The Ar or Het listed in the definitions of the substituents of thecompounds of Formula (Ia) or (Ib) (see for instance R³) as mentionedhereinbefore or hereinafter may be attached to the remainder of themolecule of Formula (Ia) or (Ib) through any ring carbon or heteroatomas appropriate, if not otherwise specified. Thus, for example, when Hetis imidazolyl, it may be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl andthe like.

Lines drawn from substituents into ring systems indicate that the bondmay be attached to any of the suitable ring atoms.

The pharmaceutically acceptable acid addition salts are defined tocomprise the therapeutically active non-toxic acid addition salt formswhich the compounds according to either Formula (Ia) or (Ib) are able toform. Said acid addition salts can be obtained by treating the base formof the compounds according to either Formula (Ia) or (Ib) withappropriate acids, for example inorganic acids, for example hydrohalicacid, in particular hydrochloric acid, hydrobromic acid, sulfuric acid,nitric acid and phosphoric acid; organic acids, for example acetic acid,hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalicacid, malonic acid, succinic acid, maleic acid, fumaric acid, malicacid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid,salicyclic acid, p-aminosalicylic acid and pamoic acid.

The compounds according to either Formula (Ia) or (Ib) containing acidicprotons may also be converted into their therapeutically activenon-toxic base addition salt forms by treatment with appropriate organicand inorganic bases. Appropriate base salts forms comprise, for example,the ammonium salts, the alkaline and earth alkaline metal salts, inparticular lithium, sodium, potassium, magnesium and calcium salts,salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine,hybramine salts, and salts with amino acids, for example arginine andlysine.

Conversely, said acid or base addition salt forms can be converted intothe free forms by treatment with an appropriate base or acid.

The term addition salt as used in the framework of this application alsocomprises the solvates which the compounds according to either Formula(Ia) or (Ib) as well as the salts thereof, are able to form. Suchsolvates are, for example, hydrates and alcoholates.

The term “quaternary amine” as used hereinbefore defines the quaternaryammonium salts which the compounds of formula (I) are able to form byreaction between a basic nitrogen of a compound of formula (I) and anappropriate quaternizing agent, such as, for example, an optionallysubstituted alkylhalide, arylalkylhalide, alkylcarbonylhalide,Arcarbonylhalide, Hetalkylhalide or Hetcarbonylhalide, e.g. methyliodideor benzyliodide. Preferably, Het represents a monocyclic heterocycleselected from furanyl or thienyl; or a bicyclic heterocycle selectedfrom benzofuranyl or benzothienyl; each monocyclic and bicyclicheterocycle may optionally be substituted with 1, 2 or 3 substituents,each substituent independently selected from the group of halo, alkyland Ar. Preferably, the quaternizing agent is alkylhalide. Otherreactants with good leaving groups may also be used, such as alkyltrifluoromethanesulfonates, alkyl methanesulfonates, and alkylp-toluenesulfonates. A quaternary amine has a positively chargednitrogen. Pharmaceutically acceptable counterions include chloro, bromo,iodo, trifluoroacetate, acetate, triflate, sulfate, sulfonate.Preferably, the counterion is iodo. The counterion of choice can beintroduced using ion exchange resins.

Compounds of either Formula (Ia) or (Ib) and some of the intermediatecompounds invariably have at least one stereogenic center in theirstructure which may lead to at least 2 stereochemically differentstructures.

The term “stereochemically isomeric forms” as used herein defines allpossible isomeric forms which the compounds of either Formula (Ia) or(Ib) may possess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers and enantiomers of the basic molecular structure. More inparticular, stereogenic centers may have the R- or S-configuration;substituents on bivalent cyclic (partially) saturated radicals may haveeither the cis- or trans-configuration. Stereochemically isomeric formsof the compounds of either Formula (Ia) or (Ib) are obviously intendedto be embraced within the scope of this invention.

Following CAS-nomenclature conventions, when two stereogenic centers ofknown absolute configuration are present in a molecule, an R or Sdescriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) tothe lowest-numbered chiral center, the reference center. Theconfiguration of the second stereogenic center is indicated usingrelative descriptors [R*,R*] or [R*,S*], where R* is always specified asthe reference center and [R*,R*] indicates centers with the samechirality and [R*,S*] indicates centers of unlike chirality. Forexample, if the lowest-numbered chiral center in the molecule has an Sconfiguration and the second center is R, the stereo descriptor would bespecified as S—[R*,S*]. If “

” and “®” are used: the position of the highest priority substituent onthe asymmetric carbon atom in the ring system having the lowest ringnumber, is arbitrarily always in the “

” position of the mean plane determined by the ring system. The positionof the highest priority substituent on the other asymmetric carbon atomin the ring system relative to the position of the highest prioritysubstituent on the reference atom is denominated “

”, if it is on the same side of the mean plane determined by the ringsystem, or “®”, if it is on the other side of the mean plane determinedby the ring system.

When a specific stereoisomeric form is indicated, this means that saidform is substantially free, i.e. associated with less than 50%,preferably less than 20%, more preferably less than 10%, even morepreferably less than 5%, further preferably less than 2% and mostpreferably less than 1% of the other isomer(s). Thus, when a compound ofFormula (Ia) or (Ib) is for instance specified as (S), this means thatthe compound is substantially free of the (R) isomer.

The compounds of either Formula (Ia) and (Ib) may be synthesized in theform of racemic mixtures of enantiomers which can be separated from oneanother following art-known resolution procedures. The racemic compoundsof either Formula (Ia) and (Ib) may be converted into the correspondingdiastereomeric salt forms by reaction with a suitable chiral acid. Saiddiastereomeric salt forms are subsequently separated, for example, byselective or fractional crystallization and the enantiomers areliberated therefrom by alkali. An alternative manner of separating theenantiomeric forms of the compounds of either Formula (Ia) and (Ib)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

The tautomeric forms of the compounds of either Formula (Ia) or (Ib) aremeant to comprise those compounds of either Formula (Ia) or (Ib) whereine.g. an enol group is converted into a keto group (keto-enoltautomerism).

The N-oxide forms of the compounds according to either Formula (Ia) or(Ib) are meant to comprise those compounds of either Formula (Ia) or(Ib) wherein one or several nitrogen atoms are oxidized to the so-calledN-oxide, particularly those N-oxides wherein the nitrogen of the amineradical is oxidized.

The invention also comprises derivative compounds (usually called“pro-drugs”) of the pharmacologically-active compounds according to theinvention, which are degraded in vivo to yield the compounds accordingto the invention. Pro-drugs are usually (but not always) of lowerpotency at the target receptor than the compounds to which they aredegraded. Pro-drugs are particularly useful when the desired compoundhas chemical or physical properties that make its administrationdifficult or inefficient. For example, the desired compound may be onlypoorly soluble, it may be poorly transported across the mucosalepithelium, or it may have an undesirably short plasma half-life.Further discussion on pro-drugs may be found in Stella, V. J. et al.,“Prodrugs”, Drug Delivery Systems, 1985, pp. 112-176, and Drugs, 1985,29, pp. 455-473.

Pro-drugs forms of the pharmacologically-active compounds according tothe invention will generally be compounds according to either Formula(Ia) or (Ib), the pharmaceutically acceptable acid or base additionsalts thereof, the stereochemically isomeric forms thereof, thetautomeric forms thereof and the N-oxide forms thereof, having an acidgroup which is esterified or amidated. Included in such esterified acidgroups are groups of the formula —COOR^(x), where R^(x) is a C₁₋₆alkyl,phenyl, benzyl or one of the following groups:

Amidated groups include groups of the formula —CONR^(y)R^(z), whereinR^(y) is H, C₁₋₆alkyl, phenyl or benzyl and R^(z) is —OH, H, C₁₋₆alkyl,phenyl or benzyl.

Compounds according to the invention having an amino group may bederivatised with a ketone or an aldehyde such as formaldehyde to form aMannich base. This base will hydrolyze with first order kinetics inaqueous solution.

Whenever used hereinafter, the term “compounds of Formula (Ia) or (Ib)”is meant to also include their N-oxide forms, their salts, theirquaternary amines, their tautomeric forms or their stereochemicallyisomeric forms. Of special interest are those compounds of formula (Ia)or (Ib) which are stereochemically pure.

An interesting embodiment of the present invention relates to thosecompounds of Formula (Ia) or (Ib), the pharmaceutically acceptable acidor base addition salts thereof, the quaternary amines thereof, thestereochemically isomeric forms thereof, the tautomeric forms thereofand the N-oxide forms thereof, wherein

-   R¹ is hydrogen, halo, haloalkyl, cyano, hydroxy, Ar, Het, alkyl,    alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or    di(Ar)alkyl;-   p is an integer equal to 1, 2 or 3;-   R² is hydrogen; alkyl; hydroxy; mercapto; alkyloxy optionally    substituted with amino or mono or di(alkyl)amino or a radical of    formula

wherein Z is CH₂, CH—R¹⁰, O, S, N—R¹⁰ and t is an integer equal to 1 or2 and the dotted line represents an optional bond; alkyloxyalkyloxy;alkylthio; mono or di(alkyl)amino wherein alkyl may optionally besubstituted with one or two substituents each independently be selectedfrom alkyloxy or Ar or Het or morpholinyl or 2-oxopyrrolidinyl; Het or aradical of formula

wherein Z is CH₂, CH—R¹⁰, O, S, N—R¹⁰; t is an integer equal to 1 or 2;and the dotted line represents an optional bond;

-   R³ is alkyl, Ar, Ar-alkyl, Het or Het-alkyl;-   q is an integer equal to zero, 1, 2, 3 or 4;-   X is a direct bond;-   R⁴ and R⁵ each independently are hydrogen, alkyl or benzyl; or-   R⁴ and R⁵ together and including the N to which they are attached    may form a radical selected from the group of pyrrolidinyl,    2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, pyrazolidinyl, 2-imidazolinyl,    2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl,    pyridinyl, piperazinyl, imidazolidinyl, pyridazinyl, pyrimidinyl,    pyrazinyl, triazinyl, morpholinyl and thiomorpholinyl, each of said    rings optionally being substituted with alkyl, halo, haloalkyl,    hydroxy, alkyloxy, amino, mono- or dialkylamino, alkylthio,    alkyloxyalkyl, alkylthioalkyl and pyrimidinyl;-   R⁶ is a radical of formula

wherein s is an integer equal to zero, 1, 2, 3 or 4; r is an integerequal to 1, 2, 3, 4 or 5; and R¹¹ is hydrogen, halo, haloalkyl, hydroxy,Ar, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkylor di(Ar)alkyl; or two vicinal R¹¹ radicals may be taken together toform together with the phenyl ring to which they are attached anaphthyl;

-   R⁷ is hydrogen, alkyl, Ar or Het;-   R⁸ is hydrogen or alkyl;-   R⁹ is oxo; or-   R⁸ and R⁹ together form the radical —CH═CH—N═;-   R¹⁰ is hydrogen, alkyl, aminocarbonyl, mono- or    di(alkyl)aminocarbonyl, Ar,-   Het, alkyl substituted with one or two Het, alkyl substituted with    one or two Ar, Het-C(═O)—;-   alkyl is a straight or branched saturated hydrocarbon radical having    from 1 to 6 carbon atoms; or is a cyclic saturated hydrocarbon    radical having from 3 to 6 carbon atoms; or is a cyclic saturated    hydrocarbon radical having from 3 to 6 carbon atoms attached to a    straight or branched saturated hydrocarbon radical having from 1 to    6 carbon atoms; wherein each carbon atom can be optionally    substituted with hydroxy, alkyloxy or oxo;-   Ar is a homocycle selected from the group of phenyl, naphthyl,    acenaphthyl, tetrahydronaphthyl, each optionally substituted with 1,    2 or 3 substituents, each substituent independently selected from    the group of hydroxy, halo, cyano, nitro, amino, mono- or    dialkylamino, alkyl, haloalkyl, alkyloxy, haloalkyloxy, carboxyl,    alkyloxycarbonyl, alkylcarbonyl, aminocarbonyl, morpholinyl and    mono- or dialkylaminocarbonyl;-   Het is a monocyclic heterocycle selected from the group of    N-phenoxypiperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl,    thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,    pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic    heterocycle selected from the group of quinolinyl, quinoxalinyl,    indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,    benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl,    2,3-dihydrobenzo[1,4]dioxinyl or benzo[1,3]dioxolyl; each monocyclic    and bicyclic heterocycle may optionally be substituted on a carbon    atom with 1, 2 or 3 substituents, each substituent independently    selected from the group of halo, hydroxy, alkyl or alkyloxy;-   halo is a substituent selected from the group of fluoro, chloro,    bromo and iodo and-   haloalkyl is a straight or branched saturated hydrocarbon radical    having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon    radical having from 3 to 6 carbon atoms or a cyclic saturated    hydrocarbon radical having from 3 to 6 carbon atoms attached to a    straight or branched saturated hydrocarbon radical having from 1 to    6 carbon atoms; wherein one or more carbon atoms are substituted    with one or more halo atoms.

Preferably, the invention relates to a compound of Formula (Ia) or (Ib)or any subgroup thereof as mentioned hereinbefore as interestingembodiment wherein R¹¹ is hydrogen, halo, haloalkyl, hydroxy, Ar, alkyl,alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkyl ordi(Ar)alkyl.

Preferably, the invention relates to a compound of Formula (Ia) or (Ib)or any subgroup thereof as mentioned hereinbefore as interestingembodiment wherein when R⁶ is other than hydrogen then R⁷ is hydrogenand when R⁷ is other than hydrogen then R⁶ is hydrogen.

Preferably, the invention relates to a compound of Formula (Ia) or (Ib)or any subgroup thereof as mentioned hereinbefore as interestingembodiment wherein R⁶ is other than hydrogen and R⁷ is hydrogen.

Preferably, the invention relates to a compound of Formula (Ia) or (Ib)or any subgroup thereof as mentioned hereinbefore as interestingembodiment wherein R⁷ is other than hydrogen and R⁶ is hydrogen.

Preferably, the invention relates to compounds of Formula (Ia) and (Ib)wherein:

-   R¹ is hydrogen, halo, cyano, Ar, Het, alkyl, and alkyloxy;-   P is an integer equal to 1, 2 or 3;-   R² is hydrogen; alkyl; hydroxy; alkyloxy optionally substituted with    amino or mono or di(alkyl)amino or a radical of formula

wherein Z is CH₂, CH—R¹⁰, O, S, N—R¹⁰ and t is an integer equal to 1 or2 and the dotted line represents an optional bond; alkyloxyalkyloxy;alkylthio; mono or di(alkyl)amino; Ar; Het or a radical of formula

wherein Z is CH₂, CH—R¹⁰, O, S, N—R¹⁰; t is an integer equal to 1 or 2;and the dotted line represents an optional bond;

-   R³ is alkyl, Ar, Ar-alkyl or Het;-   q is an integer equal to zero, 1, 2, or 3-   X is a direct bond or CH₂;-   R⁴ and R⁵ each independently are hydrogen, alkyl or benzyl; or-   R⁴ and R⁵ together and including the N to which they are attached    may form a radical selected from the group of pyrrolidinyl,    imidazolyl, triazolyl, piperidinyl, piperazinyl, pyrazinyl,    morpholinyl and thiomorpholinyl, optionally substituted with alkyl    and pyrimidinyl;-   R⁶ is hydrogen or a radical of formula

wherein s is an integer equal zero, 1, 2, 3 or 4; r is an integer equalto 1, 2, 3, 4 or 5; and R¹¹ is hydrogen, halo, or alkyl; or two vicinalR¹¹ radicals may be taken together to form together with the phenyl ringto which they are attached a naphthyl; preferably R¹¹ is hydrogen, halo,or alkyl;

-   r is an integer equal to 1;-   R⁷ is hydrogen or Ar;-   R⁸ is hydrogen or alkyl;-   R⁹ is oxo; or-   R⁸ and R⁹ together form the radical —CH═CH—N═; alkyl is a straight    or branched saturated hydrocarbon radical having from 1 to 6 carbon    atoms; or is a cyclic saturated hydrocarbon radical having from 3 to    6 carbon atoms; or is a cyclic saturated hydrocarbon radical having    from 3 to 6 carbon atoms attached to a straight or branched    saturated hydrocarbon radical having from 1 to 6 carbon atoms;    wherein each carbon atom can be optionally substituted with hydroxy;-   Ar is a homocycle selected from the group of phenyl, naphthyl,    acenaphthyl, tetrahydronaphthyl, each optionally substituted with 1,    2 or 3 substituents, each substituent independently selected from    the group of halo, haloalkyl, cyano, alkyloxy and morpholinyl;-   Het is a monocyclic heterocycle selected from the group of    N-phenoxypiperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl,    thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,    pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; or a bicyclic    heterocycle selected from the group of quinolinyl, isoquinolinyl,    1,2,3,4-tetrahydroisoquinolinyl, quinoxalinyl, indolyl, indazolyl,    benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,    benzisothiazolyl, benzofuranyl, benzothienyl,    2,3-dihydrobenzo[1,4]dioxinyl or benzo[1,3]dioxolyl; each monocyclic    and bicyclic heterocycle may optionally be substituted on a carbon    atom with 1, 2 or 3 substituents selected from the group of halo,    hydroxy, alkyl or alkyloxy; and-   halo is a substituent selected from the group of fluoro, chloro and    bromo.-   haloalkyl is a straight or branched saturated hydrocarbon radical    having from 1 to 6 carbon atoms or a cyclic saturated hydrocarbon    radical having from 3 to 6 carbon atoms or a cyclic saturated    hydrocarbon radical having from 3 to 6 carbon atoms attached to a    straight or branched saturated hydrocarbon radical having from 1 to    6 carbon atoms; wherein one or more carbon atoms are substituted    with one or more halo atoms.

Preferably, the invention relates to a compound of Formula (Ia) or (Ib)or any subgroup thereof as mentioned hereinbefore as interestingembodiment wherein R¹ is hydrogen, halo, Ar, Het, alkyl or alkyloxy.More preferably, R¹ is hydrogen, halo, alkyl or Het. Even more inparticular R¹ is hydrogen, halo or Het. Most preferably, R¹ is halo, inparticular bromo.

Preferably, the invention relates to a compound of Formula (Ia) or (Ib)or any subgroup thereof as mentioned hereinbefore as interestingembodiment wherein p is equal to 1.

Preferably, the invention relates to a compound of Formula (Ia) or (Ib)or any subgroup thereof as mentioned hereinbefore as interestingembodiment wherein R² is hydrogen; alkyl; alkyloxy optionallysubstituted with amino or mono or di(alkyl)amino or a radical of formula

wherein Z is CH₂, CH—R¹⁰, O, S, N—R¹⁰ and t is an integer equal to 1 or2 and the dotted line represents an optional bond; mono ordi(alkyl)amino wherein alkyl may optionally be substituted with one ortwo substituents each independently be selected from alkyloxy or Ar; Ar;Het or a radical of formula

wherein Z is CH₂, CH—R¹⁰, O, S, N—R¹⁰; t is an integer equal to 1 or 2;and the dotted line represents an optional bond. More preferably, R² isalkyloxy; Het; Ar; alkyl; mono or di(alkyl)amino wherein alkyl mayoptionally be substituted with one or two substituents eachindependently be selected from alkyloxy or Ar; a radical of formula

wherein Z is CH₂, CH—R¹⁰, O, N—R¹⁰; t is an integer equal to 1 or 2;alkyloxy substituted with amino or mono or di(alkyl)amino or a radicalof formula

wherein Z is CH₂, CH—R¹⁰, O, N—R¹⁰ and t is an integer equal to 1 or 2.Even more preferably, R² is alkyloxy; Het; Ar; mono or di(alkyl)aminowherein alkyl may optionally be substituted with one or two Arsubstituents; a radical of formula

wherein Z is N—R¹⁰; t is an integer equal to 2; alkyloxy substitutedwith amino or mono or di(alkyl)amino or a radical of formula

wherein Z is CH₂ and t is an integer equal to 2. Most preferably, R² isalkyloxy, e.g. methyloxy; Het or a radical of formula

wherein Z is CH₂, CH—R¹⁰, O, N—R¹⁰ and t is 1 or 2; in particular R² isalkyloxy.

Preferably, the invention relates to a compound of Formula (Ia) or (Ib)or any subgroup thereof as mentioned hereinbefore as interestingembodiment wherein R³ is naphthyl, phenyl or Het, each optionallysubstituted with 1 or 2 substituents, that substituent preferably beinga halo or haloalkyl, most preferably being a halo. More preferably, R³is naphthyl, phenyl, 3,5-dihalophenyl, 1,6-dihalophenyl, thienyl,furanyl, benzofuranyl, pyridyl. Even more preferably R³ is naphthyl,phenyl, 3,5-dihalophenyl, thienyl, furanyl or benzofuranyl. Mostpreferably, R³ is optionally substituted phenyl, e.g. 3,5-dihalophenyl,or naphthyl.

Preferably, the invention relates to a compound of Formula (Ia) or (Ib)or any subgroup thereof as mentioned hereinbefore as interestingembodiment wherein q is equal to zero, 1 or 2. More preferably, q isequal to 1.

Preferably, the invention relates to a compound of Formula (Ia) or (Ib)or any subgroup thereof as mentioned hereinbefore as interestingembodiment wherein R⁴ and R⁵ each independently are hydrogen or alkyl,more preferably hydrogen, methyl or ethyl, most preferably methyl.

Preferably, the invention relates to a compound of Formula (Ia) or (Ib)or any subgroup thereof as mentioned hereinbefore as interestingembodiment wherein R⁴ and R⁵ together and including the N to which theyare attached form a radical selected from the group of imidazolyl,triazolyl, piperidinyl, piperazinyl and thiomorpholinyl, optionallysubstituted with alkyl, halo, haloalkyl, hydroxy, alkyloxy, alkylthio,alkyloxyalkyl or alkylthioalkyl, preferably substituted with alkyl, mostpreferably substituted with methyl or ethyl.

Preferably, the invention relates to a compound of Formula (Ia) or (Ib)or any subgroup thereof as mentioned hereinbefore as interestingembodiment wherein R⁶ is hydrogen or a radical of formula

wherein s is an integer equal to zero, 1 or 2, preferably zero or 1; ris an integer equal to 1 or 2, preferably 1; and R¹¹ is hydrogen, halo,or alkyl, preferably hydrogen or alkyl. More preferably, R⁶ is a radicalof formula

Most preferably, R⁶ is benzyl or phenyl. Preferably r is 1 and R¹¹ ishydrogen.

Preferably, the invention relates to a compound of Formula (Ia) or (Ib)or any subgroup thereof as mentioned hereinbefore as interestingembodiment wherein R⁷ is hydrogen, alkyl or Ar. More preferably hydrogenor Ar, in particular hydrogen or phenyl. Most preferably R⁷ is hydrogen.

For compounds according to Formula (Ib) only, preferably, the inventionrelates to a compound of Formula (Ib) or any subgroup thereof asmentioned hereinbefore as interesting embodiment wherein R⁸ is alkyl orhydrogen, preferably hydrogen, and R⁹ is oxygen.

Preferably, the invention relates to a compound of Formula (Ia) or (Ib)or any subgroup thereof as mentioned hereinbefore as interestingembodiment wherein R¹⁰ is hydrogen, alkyl, hydroxyl, alkyl substitutedwith one or two Het, alkyl substituted with one or two Ar, Het-C(═O)—.More preferably, R¹⁰ is alkyl or Ar. Most preferably R¹⁰ is hydroxyl,Het, alkyl substituted with one Het, alkyl substituted with one Ar.

Preferably, the compounds of the present invention or any subgroupthereof as mentioned hereinbefore as interesting embodiment arecompounds according to Formula (Ia), the pharmaceutically acceptableacid or base addition salts thereof, the quaternary amines thereof, thestereochemically isomeric forms thereof, the tautomeric forms thereof orthe N-oxide forms thereof.

Preferably, the invention relates to a compound of Formula (Ia) or (Ib)or any subgroup thereof as mentioned hereinbefore as interestingembodiment wherein X is a direct bond.

Preferably, the invention relates to a compound of Formula (Ia) or (Ib)or any subgroup thereof as mentioned hereinbefore as interestingembodiment wherein X is CH₂.

Preferably, the invention relates to a compound of Formula (Ia) or (Ib)or any subgroup thereof as mentioned hereinbefore as interestingembodiment wherein R³ is other than unsubstituted phenyl when R² is Het.

Preferably, the invention relates to a compound of Formula (Ia) or (Ib)or any subgroup thereof as mentioned hereinbefore as interestingembodiment wherein the

radical is placed in position 4, 5 or 8, in particular 8.

An interesting group of compounds are those compounds according toFormula (Ia) or (Ib), preferably (Ia), the pharmaceutically acceptableacid or base addition salts thereof, the quaternary amines thereof, thestereochemically isomeric forms thereof, the tautomeric forms thereofand the N-oxide forms thereof, in which R¹ is hydrogen, halo, Ar, alkylor alkyloxy; p=1; R² is hydrogen, alkyloxy or alkylthio; R³ is naphthyl,phenyl or thienyl, each optionally substituted with 1 or 2 substituentsselected from the group of halo and haloalkyl; q=0, 1, 2 or 3; R⁴ and R⁵each independently are hydrogen or alkyl or R⁴ and R⁵ together andincluding the N to which they are attached form a radical selected fromthe group of imidazolyl, triazolyl, piperidinyl, piperazinyl andthiomorpholinyl; R⁶ is hydrogen, alkyl or halo; r is equal to 1 and R⁷is hydrogen.

Also an interesting group of compounds are those compounds according toFormula (Ia) or (Ib), preferably (Ia), the pharmaceutically acceptableacid or base addition salts thereof, the quaternary amines thereof, thestereochemically isomeric forms thereof, the tautomeric forms thereof orthe N-oxide forms thereof, wherein R¹ is hydrogen, halo, alkyl or Het,wherein Het is preferably pyridyl; R² is alkyl, alkyloxy optionallysubstituted with mono or di(alkyl)amino or a radical of formula

wherein Z is CH₂, CH—R¹⁰, O, N—R¹⁰, preferably Z is CH₂, t is an integerequal to 1 or 2, and R¹⁰ is hydrogen, alkyl, hydroxyl, alkyl substitutedwith one or two Het, alkyl substituted with one or two Ar, Het-C(═O)—,preferably R¹⁶ is hydrogen; Ar; Het; a radical of formula

wherein Z is CH₂, CH—R¹⁰, O, N—R¹⁰, t is an integer equal to 1 or 2,wherein R¹⁰ is hydrogen, alkyl, hydroxyl, alkyl substituted with one ortwo Het, alkyl substituted with one or two Ar, Het-C(═O)—; R³ is Ar,preferably phenyl or naphthyl, or Het, preferably thienyl, furanyl,pyridyl, benzofuranyl, each of said Ar or Het optionally substitutedwith 1 or 2 substituents that substituent preferably being a halo; R⁴and R⁵ are each alkyl, preferably methyl; R⁶ is hydrogen, phenyl, benzylor 4-methylbenzyl; R⁷ is hydrogen or phenyl; R⁸ is hydrogen; R⁹ is oxo.

In particular, compounds according to Formula (Ia) or (Ib), preferably(Ia), the pharmaceutically acceptable acid or base addition saltsthereof, the quaternary amines thereof, the stereochemically isomericforms thereof, the tautomeric forms thereof or the N-oxide formsthereof, wherein R¹ is hydrogen, halo or Het, wherein Het is preferablypyridyl; R² is alkyloxy optionally substituted with mono ordi(alkyl)amino or a radical of formula

wherein Z is CH₂, t is an integer equal to 2; mono or di(alkyl)aminowherein alkyl is optionally substituted with one or two Ar; a radical offormula

wherein Z is N—R¹⁰, t is an integer equal to 2; or Het; R³ is Ar,preferably phenyl or naphthyl, or Het, preferably thienyl, furanyl, orbenzofuranyl, each of said Ar or Het optionally substituted with 1 or 2substituents that substituent preferably being a halo; R⁴ and R⁵ areeach alkyl, preferably methyl; R⁶ is hydrogen, phenyl or benzyl, inparticular phenyl or benzyl; R⁷ is hydrogen.

An interesting embodiment is the use of a compound of Formula (Ia) or(Ib) or any subgroup thereof as mentioned hereinbefore as interestingembodiment for the manufacture of a medicament for the treatment of aninfection with a gram-positive and/or a gram-negative bacterium.

An interesting embodiment is the use of a compound of Formula (Ia) or(Ib) or any subgroup thereof as mentioned hereinbefore as interestingembodiment for the manufacture of a medicament for the treatment of aninfection with a gram-positive bacterium.

An interesting embodiment is the use of the compounds of Formula (Ia) or(Ib) or any subgroup thereof as mentioned hereinbefore as interestingembodiment for the manufacture of a medicament for the treatment of aninfection with a gram-negative bacterium.

An interesting embodiment is the use of a compound of Formula (Ia) or(Ib) or any subgroup thereof as mentioned hereinbefore as interestingembodiment for the manufacture of a medicament for the treatment of abacterial infection wherein the compound of Formula (Ia) or (Ib) has aIC₉₀<15 μl/ml against at least one bacterium, in particular agram-positive bacterium, preferably a IC₉₀<10 μl/ml, more preferably aIC₉₀<5 μl/ml; the IC₉₀ value being determined as described hereinafter.

Preferred compounds of the present invention are compounds 64, 8, 46,12, 10, 24, 9, 13, 22, 33, 20, 65, 19, 59, 54, 26, 66, 67, 49, 48, 70,71, 21, 6, 45, 2, 5, 4, 1, 3 as described hereinafter in theexperimental part, a pharmaceutically acceptable acid or base additionsalt thereof, a quaternary amine thereof, a stereochemically isomericform thereof, a tautomeric form thereof or a N-oxide form thereof.

The present invention also relates to the following compounds:

a pharmaceutically acceptable acid or base addition salt thereof, aquaternary amine thereof, a stereochemically isomeric form thereof, atautomeric form thereof or a N-oxide form thereof.

In general, bacterial pathogens may be classified as eithergram-positive or gram-negative pathogens. Antibiotic compounds withactivity against both gram-positive and gram-negative pathogens aregenerally regarded as having a broad spectrum of activity. The compoundsof the present invention are regarded as active against gram-positiveand/or gram-negative bacterial pathogens. In particular, the presentcompounds are active against at least one gram-positive bacterium,preferably against several gram-positive bacteria, more preferablyagainst one or more gram-positive bacteria and/or one or moregram-negative bacteria. Also intermediates of formula (II) wherein W₁represents halo, show antibacterial activity.

The present compounds have bactericidal or bacteriostatic activity.

Examples of gram-positive and gram-negative aerobic and anaerobicbacteria, include Staphylococci, for example S. aureus; Enterococci, forexample E. faecalis; Streptococci, for example S. pneumoniae, S. mutans,S. pyogens; Bacilli, for example Bacillus subtilis; Listeria, forexample Listeria monocytogenes; Haemophilus, for example H. influenza;Moraxella, for example M. catarrhalis; Pseudomonas, for examplePseudomonas aeruginosa; and Escherichia, for example E. coli.

Gram-positive pathogens, for example Staphylococci, Enterococci andStreptococci are particularly important because of the development ofresistant strains which are both difficult to treat and difficult toeradicate from for example a hospital environment once established.Examples of such strains are methicillin resistant Staphylococcus aureus(MRSA), methicillin resistant coagulase negative staphylococci (MRCNS),penicillin resistant Streptococcus pneumoniae and multiple resistantEnterococcus faecium.

The compounds of the present invention also show activity againstresistant bacterial strains.

The compounds of the present invention are especially active againstStaphylococcus aureus, including resistant Staphylococcus aureus such asfor example methicillin resistant Staphylococcus aureus (MRSA), andStreptococcus pneumoniae.

In particular, the compounds of the present invention are active onthose bacteria of which the viability depends on proper functioning ofF1F0 ATP synthase. Without being bound to any theory, it is taught thatthe activity of the present compounds lies in inhibition of the F1F0 ATPsynthase, in particular the inhibition of the F0 complex of the F1F0 ATPsynthase, more in particular the inhibition of subunit c of the F0complex of the F1F0 ATP synthase, leading to killing of the bacteria bydepletion of the cellular ATP levels of the bacteria.

Whenever used hereinbefore or hereinafter, that the compounds can treata bacterial infection it is meant that the compounds can treat aninfection with one or more bacterial strains.

Whenever used hereinbefore or hereinafter, that the bacterial infectionis other than a Mycobacterial infection it is meant that the bacterialinfection is other than an infection with one or more Mycobacteriastrains.

The exact dosage and frequency of administration of the presentcompounds depends on the particular compound of Formula (Ia) or (Ib)used, the particular condition being treated, the severity of thecondition being treated, the age, weight, gender, diet, time ofadministration and general physical condition of the particular patient,the mode of administration as well as other medication the individualmay be taking, as is well known to those skilled in the art.Furthermore, it is evident that the effective daily amount may belowered or increased depending on the response of the treated subjectand/or depending on the evaluation of the physician prescribing thecompounds of the instant invention.

The compound of the present invention may be administered in apharmaceutically acceptable form optionally in a pharmaceuticallyacceptable carrier. The compounds and compositions comprising thecompounds can be administered by routes such as topically, locally orsystemically. Systemic application includes any method of introducingthe compound into the tissues of the body, e.g., intrathecal, epidural,intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous,sublingual, rectal, and oral administration. The specific dosage ofantibacterial to be administered, as well as the duration of treatment,may be adjusted as needed.

Bacterial infections which may be treated by the present compoundsinclude, for example, central nervous system infections, external earinfections, infections of the middle ear, such as acute otitis media,infections of the cranial sinuses, eye infections, infections of theoral cavity, such as infections of the teeth, gums and mucosa, upperrespiratory tract infections, lower respiratory tract infections,genitourinary infections, gastrointestinal infections, gynecologicalinfections, septicemia, bone and joint infections, skin and skinstructure infections, bacterial endocarditis, burns, antibacterialprophylaxis of surgery, and antibacterial prophylaxis inimmunosuppressed patients, such as patients receiving cancerchemotherapy, or organ transplant patients.

Given the fact that the compounds of Formula (Ia) or (Ib) are activeagainst bacterial infections, the present compounds may be combined withother antibacterial agents in order to effectively combat bacterialinfections.

Therefore, the present invention also relates to a combination of (a) acompound of Formula (Ia) or (Ib), and (b) one or more otherantibacterial agents provided that the one or more other antibacterialagents are other than antimycobacterial agents.

The present invention also relates to a combination of (a) a compound ofFormula (Ia) or (Ib), and (b) one or more other antibacterial agentsprovided that the one or more other antibacterial agents are other thanantimycobacterial agents, for use as a medicine.

A pharmaceutical composition comprising a pharmaceutically acceptablecarrier and, as active ingredient, a therapeutically effective amount of(a) a compound of Formula (Ia) or (Ib), and (b) one or more otherantibacterial agents provided that the one or more other antibacterialagents are other than antimycobacterial agents, is also comprised by thepresent invention.

The present invention also relates to the use of a combination orpharmaceutical composition as defined above for the treatment of abacterial infection.

The present pharmaceutical composition may have various pharmaceuticalforms for administration purposes. As appropriate compositions there maybe cited all compositions usually employed for systemicallyadministering drugs. To prepare the pharmaceutical compositions of thisinvention, an effective amount of the particular compounds, optionallyin addition salt form, as the active ingredient is combined in intimateadmixture with a pharmaceutically acceptable carrier, which carrier maytake a wide variety of forms depending on the form of preparationdesired for administration. These pharmaceutical compositions aredesirable in unitary dosage form suitable, in particular, foradministration orally or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin, diluents,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral unit dosage forms in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations which are intendedto be converted, shortly before use, to liquid form preparations.

Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% by weight, more preferablyfrom 0.1 to 70% by weight of the active ingredients, and, from 1 to99.95% by weight, more preferably from 30 to 99.9 weight % of apharmaceutically acceptable carrier, all percentages being based on thetotal composition.

The weight to weight ratio's of the compound of Formula (Ia) or (Ib) and(b) the other antibacterial agent(s) when given as a combination may bedetermined by the person skilled in the art. Said ratio and the exactdosage and frequency of administration depends on the particularcompound of Formula (Ia) or (Ib) and the other antibacterial agent(s)used, the particular condition being treated, the severity of thecondition being treated, the age, weight, gender, diet, time ofadministration and general physical condition of the particular patient,the mode of administration as well as other medication the individualmay be taking, as is well known to those skilled in the art.Furthermore, it is evident that the effective daily amount may belowered or increased depending on the response of the treated subjectand/or depending on the evaluation of the physician prescribing thecompounds of the instant invention.

The compounds of Formula (Ia) or (Ib) and the one or more otherantibacterial agents may be combined in a single preparation or they maybe formulated in separate preparations so that they can be administeredsimultaneously, separately or sequentially. Thus, the present inventionalso relates to a product containing (a) a compound of Formula (Ia) or(Ib), and (b) one or more other antibacterial agents provided that theone or more other antibacterial agents are other than antimycobacterialagents, as a combined preparation for simultaneous, separate orsequential use in the treatment of a bacterial infection.

The pharmaceutical composition may additionally contain various otheringredients known in the art, for example, a lubricant, stabilisingagent, buffering agent, emulsifying agent, viscosity-regulating agent,surfactant, preservative, flavouring or colorant.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage.

Unit dosage form as used herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such unit dosage forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,suppositories, injectable solutions or suspensions and the like, andsegregated multiples thereof. The daily dosage of the compound accordingto the invention will, of course, vary with the compound employed, themode of administration, the treatment desired and the bacterial diseaseindicated.

The other antibacterial agents which may be combined with the compoundsof formula (I) are antibacterial agents known in the art. The otherantibacterial agents comprise antibiotics of the β-lactam group such asnatural penicillins, semisynthetic penicillins, natural cephalosporins,semisynthetic cephalosporins, cephamycins, 1-oxacephems, clavulanicacids, penems, carbapenems, nocardicins, monobactams; tetracyclines,anhydrotetracyclines, anthracyclines; aminoglycosides; nucleosides suchas N-nucleosides, C-nucleosides, carbocyclic nucleosides, blasticidin S;macrolides such as 12-membered ring macrolides, 14-membered ringmacrolides, 16-membered ring macrolides; ansamycins; peptides such asbleomycins, gramicidins, polymyxins, bacitracins, large ring peptideantibiotics containing lactone linkages, actinomycins, amphomycin,capreomycin, distamycin, enduracidins, mikamycin, neocarzinostatin,stendomycin, viomycin, virginiamycin; cycloheximide; cycloserine;variotin; sarkomycin A; novobiocin; griseofulvin; chloramphenicol;mitomycins; fumagillin; monensins; pyrrolnitrin; fosfomycin; fusidicacid; D-(p-hydroxyphenyl)glycine; D-phenylglycine; enediynes.

Specific antibiotics which may be combined with the present compounds offormula (Ia) or (Ib) are for example benzylpenicillin (potassium,procaine, benzathine), phenoxymethylpenicillin (potassium),phenethicillin potassium, propicillin, carbenicillin (disodium, phenylsodium, indanyl sodium), sulbenicillin, ticarcillin disodium,methicillin sodium, oxacillin sodium, cloxacillin sodium, dicloxacillin,flucloxacillin, ampicillin, mezlocillin, piperacillin sodium,amoxicillin, ciclacillin, hectacillin, sulbactam sodium, talampicillinhydrochloride, bacampicillin hydrochloride, pivmecillinam, cephalexin,cefaclor, cephaloglycin, cefadroxil, cephradine, cefroxadine, cephapirinsodium, cephalothin sodium, cephacetrile sodium, cefsulodin sodium,cephaloridine, cefatrizine, cefoperazone sodium, cefamandole, vefotiamhydrochloride, cefazolin sodium, ceftizoxime sodium, cefotaxime sodium,cefmenoxime hydrochloride, cefuroxime, ceftriaxone sodium, ceftazidime,cefoxitin, cefmetazole, cefotetan, latamoxef, clavulanic acid, imipenem,aztreonam, tetracycline, chlortetracycline hydrochloride,demethylchlortetracycline, oxytetracycline, methacycline, doxycycline,rolitetracycline, minocycline, daunorubicin hydrochloride, doxorubicin,aclarubicin, kanamycin sulfate, bekanamycin, tobramycin, gentamycinsulfate, dibekacin, amikacin, micronomicin, ribostamycin, neomycinsulfate, paromomycin sulfate, streptomycin sulfate, dihydrostreptomycin,destomycin A, hygromycin B, apramycin, sisomicin, netilmicin sulfate,spectinomycin hydrochloride, astromicin sulfate, validamycin,kasugamycin, polyoxin, blasticidin S, erythromycin, erythromycinestolate, oleandomycin phosphate, tracetyloleandomycin, kitasamycin,josamycin, spiramycin, tylosin, ivermectin, midecamycin, bleomycinsulfate, peplomycin sulfate, gramicidin S, polymyxin B, bacitracin,colistin sulfate, colistinmethanesulfonate sodium, enramycin, mikamycin,virginiamycin, capreomycin sulfate, viomycin, enviomycin, vancomycin,actinomycin D, neocarzinostatin, bestatin, pepstatin, monensin,lasalocid, salinomycin, amphotericin B, nystatin, natamycin,trichomycin, mithramycin, lincomycin, clindamycin, clindamycin palmitatehydrochloride, flavophospholipol, cycloserine, pecilocin, griseofulvin,chloramphenicol, chloramphenicol palmitate, mitomycin C, pyrrolnitrin,fosfomycin, fusidic acid, bicozamycin, tiamulin, siccanin.

General Preparation

The compounds according to the invention can generally be prepared by asuccession of steps, each of which is known to the skilled person.

Compounds of Formula (Ia) wherein R² represents alkoxy; a radical offormula

wherein t and Z are defined as hereinabove; alkyloxy substituted with aradical of formula

wherein t and Z are defined as hereinabove; mono or di(alkyl)aminowherein alkyl may optionally be substituted with one or two substituentseach independently be selected from alkyloxy or Ar or Het or morpholinylor 2-oxopyrrolidinyl, said R² being represented by R^(2a), and saidcompounds being represented by Formula (Ia-1), can be prepared byreacting an intermediate of formula (II), wherein W₁ represents asuitable leaving group, such as for example halo, e.g. chloro and thelike, with H—R^(2a) or with a suitable salt form of R^(2a)—H optionallyin the presence of a suitable solvent, such as for example an alcohol,e.g. methanol and the like, acetonitrile, and optionally in the presenceof a suitable base, such as for example KOH, dipotassium carbonate.

Compounds of Formula (Ia) wherein R² represents Het or alkyl, said R²being represented by formula R^(2b) and said compounds being representedby Formula (Ia-2), can be prepared by reacting an intermediate offormula (II) with R^(2b)—B(OH)₂, in the presence of a suitable catalyst,such as for example Pd(PPh₃)₄, a suitable solvent, such as for exampledimethylether or an alcohol, e.g. methanol and the like, and a suitablebase, such as for example disodium carbonate or dipotassium carbonate.

Compounds of Formula (Ia) wherein R² represents Het, e.g. pyridyl, saidR² being represented by Het and said intermediates being represented byFormula (Ia-3) can be prepared by reacting an intermediate of formula(II) with

in the presence of a suitable catalyst, such as for example Pd(PPh₃)₄, asuitable solvent, such as for example dimethylether or an alcohol, e.g.methanol and the like, and a suitable base, such as for example disodiumcarbonate or dipotassium carbonate.

Compounds of Formula (Ia) wherein X is a direct bond, said intermediatesbeing represented by Formula (Ia-4), can be prepared by reacting anintermediate of formula (III) wherein W₂ represents a suitable leavinggroup, such as for example halo, e.g. bromo, chloro and the like, withan intermediate of formula (IV) in the presence of a suitable couplingagent, such as for example n-butyl lithium, secBuLi, and in the presenceof a suitable solvent, such as for example tetrahydrofuran, andoptionally in the presence of a suitable base, such as for example2,2,6,6-tetramethylpiperidine, NH(CH₂CH₂CH₃)₂, N,N-diisopropylamine ortrimethylethylenediamine.

Compounds of Formula (Ib) wherein R⁹ represents oxo, can be prepared byreacting an intermediate of formula (II) with a suitable acid, such asfor example HCl, in the presence of a suitable solvent, such as forexample tetrahydrofuran.

Compounds of Formula (Ia) or (Ib) wherein X represents CH₂, saidcompounds being represented by Formula (Ia-5) or (Ib-1), can be preparedby reacting an intermediate of formula (XX) or (XXI) with anintermediate of formula (IV) in the presence of a suitable couplingagent, such as nBuLi, secBuLi, and in the presence of a suitablesolvent, such as for example tetrahydrofuran, and optionally a suitablebase, such as for example 2,2,6,6-tetramethylpiperidine, NH(CH₂CH₂CH₃)₂,N,N-diisopropylamine or trimethylethylenediamine.

In the above reactions, the obtained compound of Formula (Ia) or (Ib)can be isolated, and, if necessary, purified according to methodologiesgenerally known in the art such as, for example, extraction,crystallization, distillation, trituration and chromatography. In casethe compound of Formula (Ia) or (Ib) crystallizes out, it can beisolated by filtration. Otherwise, crystallization can be caused by theaddition of an appropriate solvent, such as for example water;acetonitrile; an alcohol, such as for example methanol, ethanol; andcombinations of said solvents. Alternatively, the reaction mixture canalso be evaporated to dryness, followed by purification of the residueby chromatography (e.g. reverse phase HPLC, flash chromatography and thelike). The reaction mixture can also be purified by chromatographywithout previously evaporating the solvent. The compound of Formula (Ia)or (Ib) can also be isolated by evaporation of the solvent followed byrecrystallisation in an appropriate solvent, such as for example water;acetonitrile; an alcohol, such as for example methanol; and combinationsof said solvents.

The person skilled in the art will recognise which method should beused, which solvent is the most appropriate to use or it belongs toroutine experimentation to find the most suitable isolation method.

The compounds of Formula (Ia) or (Ib) may further be prepared byconverting compounds of Formula (Ia) or (Ib) into each other accordingto art-known group transformation reactions.

The compounds of Formula (Ia) or (Ib) may be converted to thecorresponding N-oxide forms following art-known procedures forconverting a trivalent nitrogen into its N-oxide form. Said N-oxidationreaction may generally be carried out by reacting the starting materialof Formula (Ia) or (Ib) with an appropriate organic or inorganicperoxide. Appropriate inorganic peroxides comprise, for example,hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g.sodium peroxide, potassium peroxide; appropriate organic peroxides maycomprise peroxy acids such as, for example, benzenecarboperoxoic acid orhalo substituted benzenecarboperoxoic acid, e.g.3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g.peroxoacetic acid, alkylhydroperoxides, e.g. t.butyl hydro-peroxide.Suitable solvents are, for example, water, lower alcohols, e.g. ethanoland the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone,halogenated hydrocarbons, e.g. dichloromethane, and mixtures of suchsolvents.

Compounds of Formula (Ia) wherein R¹ represents halo, said compoundsbeing represented by Formula (Ia-6), can be converted into a compound ofFormula (Ia) wherein R¹ represents Het, e.g. pyridyl, said compoundsbeing represented by Formula (Ia-7), by reaction with

in the presence of a suitable catalyst, such as for example Pd(PPh₃)₄, asuitable solvent, such as for example dimethylether or an alcohol, e.g.methanol and the like, and a suitable base, such as for example disodiumcarbonate or dipotassium carbonate.

Compounds of Formula (Ia-6) can also be converted into a compound ofFormula (Ia) wherein R¹ represents methyl, said compound beingrepresented by Formula (Ia-8), by reaction with Sn(CH₃)₄ in the presenceof a suitable catalyst, such as for example Pd(PPh₃)₄, a suitablesolvent, such as for example toluene.

Some of the compounds of Formula (Ia) or (Ib) and some of theintermediates in the present invention may consist of a mixture ofstereochemically isomeric forms. Pure stereochemically isomeric forms ofsaid compounds and said intermediates can be obtained by the applicationof art-known procedures. For example, diastereoisomers can be separatedby physical methods such as selective crystallization or chromatographictechniques, e.g. counter current distribution, liquid chromatography andthe like methods. Enantiomers can be obtained from racemic mixtures byfirst converting said racemic mixtures with suitable resolving agentssuch as, for example, chiral acids, to mixtures of diastereomeric saltsor compounds; then physically separating said mixtures of diastereomericsalts or compounds by, for example, selective crystallization orchromatographic techniques, e.g. liquid chromatography and the likemethods; and finally converting said separated diastereomeric salts orcompounds into the corresponding enantiomers. Pure stereochemicallyisomeric forms may also be obtained from the pure stereochemicallyisomeric forms of the appropriate intermediates and starting materials,provided that the intervening reactions occur stereospecifically.

An alternative manner of separating the enantiomeric forms of thecompounds of Formula (Ia) or (Ib) and intermediates involves liquidchromatography, in particular liquid chromatography using a chiralstationary phase.

It is to be understood that in the above or the following preparations,the reaction products may be isolated from the reaction medium and, ifnecessary, further purified according to methodologies generally knownin the art such as, for example, extraction, crystallization,distillation, trituration and chromatography.

Some of the intermediates and starting materials are known compounds andmay be commercially available or may be prepared according to art-knownprocedures or procedures described in WO2004/011436 or WO2005/070430,which is incorporated herein by reference.

Intermediates of formula (II) wherein X is a direct bond, suchintermediates being represented by formula (II-a), can be prepared byreacting an intermediate of formula (V) wherein W₁ is as definedhereinabove, with an intermediate of formula (IV) in the presence of asuitable coupling agent, such as nBuLi, secBuLi, and in the presence ofa suitable solvent, such as for example tetrahydrofuran, and a suitablebase, such as for example 2,2,6,6-tetramethylpiperidine, NH(CH₂CH₂CH₃)₂,N,N-diisopropylamine or trimethylethylenediamine

Intermediates of formula (II) wherein X represents CH₂, saidintermediates being represented by formula (II-b), can be prepared byreacting an intermediate of formula (VI) with an intermediate of formula(IV) in the presence of a suitable coupling agent, such as nBuLi,secBuLi, and in the presence of a suitable solvent, such as for exampletetrahydrofuran, and a suitable base, such as for example2,2,6,6-tetramethylpiperidine, NH(CH₂CH₂CH₃)₂, N,N-diisopropylamine ortrimethylethylenediamine.

Intermediates of formula (II) wherein R¹ is hydrogen, said intermediatesbeing represented by formula (II-c), can be prepared by reacting anintermediate of formula (V) wherein R¹ is halo, said intermediates beingrepresented by formula (V-a), with an intermediate of formula (IV), inthe presence of a suitable strong base, such as for example nBuLi,secBuLi, and in the presence of a suitable solvent, such as for exampletetrahydrofuran.

The intermediates of formula (V) are compounds that are eithercommercially available or may be prepared according to conventionalreaction procedures generally known in the art. For example,intermediates of formula (V) wherein R⁷ is hydrogen, R⁶ is a radical offormula

wherein s is an integer equal to 1 and W₁ is chloro, said intermediatesbeing represented by formula (V-b) may be prepared according to thefollowing reaction scheme (1):

wherein all variables are defined as in Formula (Ia). Reaction scheme(1) comprises step (a) in which an appropriately substituted aniline isreacted with an appropriate acylchloride such as 3-phenylpropionylchloride, 3-fluorobenzenepropionyl chloride or p-chlorobenzenepropionylchloride, in the presence of a suitable base, such as triethylamine anda suitable reaction-inert solvent, such as methylene chloride orethylene dichloride. The reaction may conveniently be carried out at atemperature ranging between room temperature and reflux temperature. Ina next step (b) the adduct obtained in step (a) is reacted withphosphoryl chloride (POCl₃) in the presence of a suitable solvent, suchas for example N,N-dimethylformamide (Vilsmeier-Haack formylationfollowed by cyclization). The reaction may conveniently be carried outat a temperature ranging between room temperature and refluxtemperature.

It is evident that in the foregoing and in the following reactions, thereaction products may be isolated from the reaction medium and, ifnecessary, further purified according to methodologies generally knownin the art, such as extraction, crystallization and chromatography. Itis further evident that reaction products that exist in more than oneenantiomeric form, may be isolated from their mixture by knowntechniques, in particular preparative chromatography, such aspreparative HPLC. Typically, compounds of Formula (Ia) and (Ib) may beseparated into their isomeric forms.

Intermediates of formula (V-a) wherein W₁ represents chloro, saidintermediates being represented by formula (V-a-1), can be prepared byreacting an intermediate of formula (VII) with POCl₃.

Intermediates of formula (VII) can be prepared by reacting anintermediate of formula (VIII) with 4-methylbenzenesulfonyl chloride inthe presence of a suitable solvent, such as for example methylenechloride, and a suitable base, such as for example dipotassiumcarbonate.

Intermediates of formula (VIII) can be prepared by reacting anintermediate of formula (IX) with a suitable oxidizing agent, such asfor example 3-chlorobenzenecarboperoxoic acid, in the presence of asuitable solvent, such as for example methylene chloride.

Intermediates of formula (IX) wherein R⁶ is hydrogen and R⁷ is phenyl,said intermediates being represented by formula (IX-a), can be preparedby reacting an intermediate of formula (X) with3-chloro-1-phenyl-1-propanone in the presence of a suitable acid, suchas for example hydrochloric acid, iron chloride hexahydrate, zincchloride and a suitable solvent, such as for example diethyl ether and asuitable alcohol, e.g. ethanol.

Intermediates of formula (IX) wherein R⁷ is hydrogen and R⁶ is a radicalof formula

wherein s is an integer equal to 1, said intermediates being representedby formula (IX-b), can be prepared by reacting an intermediate offormula (XI) in the presence of diphenyl ether.

Intermediates of formula (XI) can be prepared by reacting anintermediate of formula (XII) with an intermediate of formula (XIII) inthe presence of a suitable base, such as for example sodium hydroxide.

Intermediates of formula (IV) are compounds that are either commerciallyavailable or may be prepared according to conventional reactionprocedures generally known in the art. For example, intermediatecompounds of formula (IV) wherein q is equal to 1, said intermediatesbeing represented by formula (IV-a), can be prepared according to thefollowing reaction scheme (2):

Reaction scheme (2) comprises step (a) in which an appropriate R³ isreacted by Friedel-Craft reaction with an appropriate acylchloride suchas 3-chloropropionyl chloride or 4-chlorobutyryl chloride, in thepresence of a suitable Lewis acid, such as AlCl₃, FeCl₃, SnCl₄, TiCl₄ orZnCl₂ and a suitable reaction-inert solvent, such as methylene chlorideor ethylene dichloride. The reaction may conveniently be carried out ata temperature ranging between room temperature and reflux temperature.In a next step (b) an amino group (e.g. —NR⁴R⁵) is introduced byreacting the intermediate compound obtained in step (a) with anappropriate amine HNR⁴R⁵.

Intermediates of formula (IV-a) can also be prepared by reacting anintermediate of formula (XIV) with HC(═O)H and a suitable amino groupHNR⁴R⁵, such as for example NH(CH₃)₂.HCl in the presence of a suitablesolvent, such as for example an alcohol, e.g. methanol, ethanol and thelike, and a suitable acid, such as for example hydrochloric acid.

Intermediates of formula (VI) wherein W₁ represents chloro, saidintermediates being represented by formula (VI-a) can be prepared byreacting an intermediate of formula (XV) with POCl₃ in the presence ofbenzyltriethylammonium chloride (Phase transfer agent) and a suitablesolvent, such as for example acetonitrile.

Intermediates of formula (XV) wherein R⁶ represents a radical of formulawherein s is an integer equal to 1, said intermediates being representedby formula (XV-a), can be prepared by reacting an intermediate offormula (XVI) with NH₂—NH₂ in the presence of a suitable base, such asfor example potassium hydroxide and a suitable solvent such as forexample 1 2-ethanediol.

which is an intermediate of formula (XVI) can be prepared by reacting1-(2-aminophenyl)ethanone and β-oxobenzenepropanoic acid ethyl ester.

Intermediates of formula (III) wherein R² represents C₁₋₆alkyloxy, saidintermediates being represented by formula (III-a), can be prepared byreacting an intermediate of formula (XVII) with the appropriateC₁₋₆alkylO-salt in the presence of a suitable solvent, such as forexample the corresponding C₁₋₆alkylOH.

Intermediates of formula (XVII) can be prepared by reacting anintermediate of formula (XVIII) with POCl₃.

Intermediates of formula (XVIII) wherein R⁷ is hydrogen and R⁶represents a radical of formula

wherein s is an integer equal to 0, said intermediates being representedby formula (XVIII-a), can be prepared by cyclization of an intermediateof formula (XIX) in the presence of AlCl₃ and a suitable solvent, suchas for example chlorobenzene.

In the intermediates of formula (III) the R¹ substituent may representhalo and then this halo substituent may take the place of the W₂ leavinggroup. Said intermediates of formula (III) being represented by formula

Intermediates of formula (XX) wherein R₂ represents C₁₋₆alkyloxy, saidintermediates being represented by formula (XX-a), can be prepared byreacting an intermediate of formula (VI-a) with C₁₋₆alkyloxy Na, in asuitable alcohol, such as C₁₋₆alkylOH.

The following examples illustrate the present invention without beinglimited thereto.

EXPERIMENTAL PART

Of some compounds the absolute stereochemical configuration of thestereogenic carbon atom(s) therein was not experimentally determined. Inthose cases the stereochemically isomeric form which was first isolatedis designated as “A” and the second as “B”, without further reference tothe actual stereochemical configuration. However, said “A” and “B”isomeric forms can be unambiguously characterized by a person skilled inthe art, using art-known methods such as, for example, X-raydiffraction. The isolation method is described in detail below.

For the synthesis of the present compounds, reference is made toWO2005/070430, which is incorporated herein by reference.

Hereinafter, the term ‘M.P.’ means melting point, ‘DIPE’ meansdiisopropyl ether, ‘DMF’ means N,N-dimethylformamide, ‘THF’ meanstetrahydrofuran, ‘EtOAc’ means ethyl acetate, ‘DCM’ meansdichloromethane.

A. Preparation of the Intermediates Example A1 Preparation ofIntermediate 1

Benzenepropanoyl chloride (0.488 mol) was added dropwise at roomtemperature to a solution of 4-bromo benzenamine (0.407 mol) in Et₃N (70ml) and DCM (700 ml) and the mixture was stirred at room temperatureovernight. The mixture was poured out into water and concentrated NH₄OH,and extracted with DCM. The organic layer was dried (MgSO₄), filtered,and the solvent was evaporated. The residue was crystallized fromdiethyl ether. The residue (119.67 g) was taken up in DCM and washedwith HCl 1N. The organic layer was dried (MgSO₄), filtered, and thesolvent was evaporated, yielding 107.67 g of intermediate 1 (87%).

Example A2 Preparation of Intermediate 2

Phosphoric trichloride (1.225 mol) was added dropwise at 10° C. to DMF(0.525 mol). Then intermediate 1 (0.175 mol) was added at roomtemperature. The mixture was stirred overnight at 80° C., poured out onice and extracted with DCM. The organic layer was dried (MgSO₄),filtered, and the solvent was evaporated. The product was used withoutfurther purification, yielding 77.62 g of intermediate 2 (67%).

Example A3 a) Preparation of Intermediate 3

A mixture of intermediate 2 (0.233 mol) in a 30% MeONa in MeOH solution(222.32 ml) and MeOH (776 ml) was stirred and refluxed overnight, thenpoured out on ice and extracted with DCM. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:DCM/cyclohexane 20/80 and then 100/0; 20-45 μm). The pure fractions werecollected and the solvent was evaporated, yielding 25 g of intermediate3 (33%).

The following intermediate was prepared according to the methoddescribed above.

intermediate 29

b) Preparation of Intermediate 4

A mixture of intermediate 2 (0.045 mol) in a 21% EtONa in EtOH solution(50 ml) and EtOH (150 ml) was stirred and refluxed for 12 hours. Themixture was poured out on ice and extracted with DCM. The organic layerwas separated, dried (MgSO₄), filtered and the solvent was evaporated,yielding 15.2 g of intermediate 4 (98%).

Example A4 a) Preparation of Intermediate 5

Aluminum chloride (1.31 mol) was added at room temperature to a mixtureof N-(3-bromophenyl)-α-(phenylmethylene)benzeneacetamide (0.1311 mol) inchlorobenzene (500 ml). The mixture was stirred and refluxed for 3hours, then cooled to room temperature, poured out into ice water andfiltered. The filtrate was washed with H₂O, then with cyclohexane anddried, yielding 35.5 g of intermediate 5 (95%).

b) Preparation of Intermediate 6 and Intermediate 7

A mixture of intermediate 5 (0.2815 mol) in phosphoric trichloride (320ml) was stirred and refluxed for 1 hour, then cooled to room temperatureand the solvent was evaporated till dryness. The residue was taken up inH₂O. The mixture was extracted with DCM. The organic layer wasseparated, dried (MgSO₄), filtered, and the solvent was evaporated tilldryness. The residue (58.2 g) was purified by column chromatography oversilica gel (eluent: toluene/cyclohexane 80/20; 15-35 μm). Two fractionswere collected and the solvent was evaporated, yielding 21 g ofintermediate 6 and 34.5 g of intermediate 7.

c) Preparation of Intermediate 8

A mixture of intermediate 6 (0.0659 mol) and a 30% MeONa in MeOHsolution (0.329 mol) in MeOH (300 ml) was stirred and refluxed for 2days, then cooled to room temperature, poured out into ice water andfiltered. The filtrate was washed with H₂O and dried, yielding 19 g ofintermediate 8 (92%).

Example A5 a) Preparation of Intermediate 9

A mixture of 5-bromo-1H-indole-2,3-dione (0.28 mol) in 3N NaOH (650 ml)was stirred and heated at 80° C. for 30 minutes, then cooled to roomtemperature. Benzenepropanal (0.28 mol) was added and the mixture wasstirred and refluxed overnight. The mixture was allowed to cool to roomtemperature and acidified till pH 5 with HOAc. The precipitate wasfiltered off, washed with H₂O and dried (vacuum), yielding 50 g ofintermediate 9 (52%).

b) Preparation of Intermediate 10

A mixture of intermediate 9 (0.035 mol) in 1,1′-oxybisbenzene (100 ml)was stirred and heated at 300° C. for 8 hours, then allowed to cool toroom temperature. This procedure was carried out four times. The fourmixtures were combined and then purified by column chromatography oversilica gel (eluent: DCM/MeOH 100/0, then 99/1). The pure fractions werecollected and the solvent was evaporated, yielding 25.6 g ofintermediate 10 (61%).

Example A6 a) Preparation of Intermediate 11

HCl/diethyl ether (30 ml) was added to a solution of 4-bromobenzenamine(0.139 mol) in EtOH (250 ml) and the mixture was stirred for 30 minutes.Iron chloride hexahydrate (0.237 mol) and then zinc chloride (0.014 mol)were added and the mixture was stirred at 80° C. for 30 minutes.3-Chloro-1-phenyl-1-propanone (0.146 mol) was added and the mixture wasstirred at 80° C. for one night. The mixture was poured into water andextracted with EtOAc. The organic layer was washed with water, then withK₂CO₃ 10%, dried (MgSO₄), filtered off and evaporated. The residue (25g) was purified by column chromatography over silica gel (eluent:DCM/MeOH 100/0 and then 97/3) (35-70 μm). The pure fractions werecollected and evaporated, yielding 17.5 g of intermediate 11 (44%).

b) Preparation of Intermediate 12

3-Chlorobenzenecarboperoxoic acid (0.12 mol) was added portionwise atroom temperature to a solution of intermediate 11 (0.0598 mol) in DCM(200 ml) and the mixture was stirred at room temperature for one night.K₂CO₃ 10% was added, the organic layer was decanted, dried (MgSO₄),filtered off and evaporated till a volume of 150 ml of intermediate 12was left.

c) Preparation of Intermediate 13

4-Methylbenzenesulfonyl chloride (0.075 mol) was added portionwise atroom temperature to a solution of intermediate 12 (0.0598 mol) in a 10%K₂CO₃ solution (150 ml) and DCM (150 ml) and the mixture was stirred atroom temperature for one night. Diethyl ether was added and filteredoff. The precipitate was washed with diethyl ether and evaporated tilldryness, yielding 14 g of intermediate 13 (78%).

d) Preparation of Intermediate 14

A mixture of intermediate 13 (0.047 mol) in phosphoric trichloride (150ml) was stirred and refluxed for 48 hours. The mixture was evaporated,the residue was taken up in NH₄OH and extracted with DCM. The organiclayer was dried (MgSO₄), filtered off and evaporated, yielding 13 g ofintermediate 14 (87%).

Example A7 a) Preparation of Intermediate 15

A mixture of 1-(2-aminophenyl)ethanone (0.37 mol) andβ-oxobenzenepropanoic acid ethyl ester (1.48 mol) was stirred at 180° C.overnight. The mixture was brought to room temperature. The precipitatewas filtered, washed with diethyl ether and dried. The residue wascrystallized from DIPE. The precipitate was filtered off and dried,yielding 56.6 g of intermediate 15 (58%).

b) Preparation of Intermediate 16

A mixture of intermediate 15 (0.076 mol) and hydrazine (0.76 mol) in1,2-ethanediol (240 ml) was stirred at 100° C. for 1 hour. KOH (0.266mol) was added. The mixture was stirred at 180° C. overnight. H₂O wasadded. The mixture was acidified and extracted with DCM. The organiclayer was separated, dried (MgSO₄), filtered, and the solvent wasevaporated. The residue (12.05 g) was crystallized from DIPE. Theprecipitate was filtered off and dried, yielding 4.74 g of intermediate16.

c) Preparation of Intermediate 17

Phosphoric trichloride (0.057 mol) was added slowly at 80° C. to amixture of intermediate 16 (0.019 mol) and benzyltriethylammoniumchloride (0.0532 mol) in acetonitrile (50 ml). The mixture was stirredovernight. The solvent was evaporated. The mixture was poured out intoice and Na₂CO₃ 10% and extracted with DCM. The organic layer wasseparated, dried (MgSO₄), filtered, and the solvent was evaporated,yielding 4.08 g of intermediate 17.

d) Preparation of Intermediate 17a

A mixture of intermediate 17 (0.0153 mol) and sodium methoxide (30 wt %solution in MeOH, 7 ml) in MeOH (35 ml) was stirred at 80° C. for 24hours. Water was added. The mixture was extracted with EtOAc. Theorganic layer was separated, dried over magnesium sulfate, filtered andthe solvent was evaporated till dryness. The residue was crystallizedfrom diisopropylether. The precipitate was filtered off and dried.Yield: 2.77 g of intermediate 17a (69%).

Example A8 a) Preparation of Intermediate 18 and Intermediate 19

A mixture of aluminium chloride (0.257 mol) and 3-chloropropanoylchloride (0.234 mol) in 1,2-dichloroethane (100 ml) was stirred at 0° C.A solution of naphthalene (0.234 mol) in 1,2-dichloroethane (100 ml) wasadded. The mixture was stirred at 0° C. for 1 hour and poured out intoice water. The organic layer was separated, dried (MgSO₄), filtered, andthe solvent was evaporated. The residue (56 g) was purified by columnchromatography over silica gel (eluent: cyclohexane/DCM 60/40; 20-45μm). Two fractions were collected and the solvent was evaporated,yielding 2 fractions, 31 g of fraction 1 as intermediate 18 (61%) and 14g of fraction 2. Fraction 2 was taken up in DIPE, then the resultingprecipitate was filtered off and dried, yielding 8.2 g of intermediate19.

b) Preparation of Intermediate 20

A mixture of intermediate 18 (0.0137 mol), N-methylbenzenemethanamine(0.015 mol) and K₂CO₃ (2 g) in acetonitrile (100 ml) was stirred at 80°C. for 2 hours. H₂O was added. The mixture was extracted with DCM. Theorganic layer was separated, dried (MgSO₄), filtered, and the solventwas evaporated, yielding 4.2 g of intermediate 20 (100%).

Example A9 Preparation of Intermediate 21

A mixture of 1-(3,5-difluorophenyl)ethanone (0.013 mol), formaldehyde(0.05 mol) and N-methylmethanamine hydrochloride (0.052 mol) inconcentrated HCl (0.1 ml) in EtOH (20 ml) was stirred at 80° C. for 20hours, then cooled to room temperature. The solvent was evaporated tilldryness. The residue was taken up in HCl 3N. The mixture was washed withdiethyl ether, basified with K₂CO₃ and extracted with diethyl ether. Theorganic layer was separated, dried (MgSO₄), filtered, and the solventwas evaporated, yielding 2 g of intermediate 21.

Example A10 a) Preparation of Intermediate 22 and Intermediate 23

1.6M Butyllithium (0.12 mol) was added dropwise at −10° C. under N₂ flowto a solution of 2,2,6,6-tetramethylpiperidine (0.12 mol) in THF (200ml). The mixture was stirred at −10° C. for 20 minutes and then cooledto −70° C. A mixture of intermediate 2 (0.1 mol) in THF (100 ml) wasadded. The mixture was stirred at −70° C. for 45 minutes. A solution of3-(dimethylamino)-1-phenyl-1-propanone (0.1 mol) in THF (100 ml) wasadded. The mixture was stirred at −70° C. for 1 hour, brought to −50° C.and hydrolysed. H₂O (100 ml) was added at −50° C. The mixture wasstirred at room temperature for 30 minutes and extracted with EtOAc. Theorganic layer was separated, dried (MgSO₄), filtered and the solvent wasevaporated. The residue was taken up in EtOAc. The precipitate wasfiltered off, washed with EtOAc and diethyl ether and dried in vacuo,yielding 4 g of intermediate 23 (8%). The mother layer was evaporated.The residue (26 g) was purified by column chromatography over silica gel(eluent: DCM/MeOH/NH₄OH 97/3/0.1; 15-40 μm). The desired fractions werecollected and the solvent was evaporated. The residue was crystallizedfrom diethyl ether. The precipitate was filtered off and dried, yielding1 g of intermediate 22.

The following intermediates were prepared according to the methoddescribed above.

intermediate 30

intermediate 31

b) Preparation of Intermediate 24

1.6M Butyllithium (0.0094 mol) was added dropwise at −20° C. to amixture of 2,2,6,6-tetramethylpiperidine (0.0094 mol) in THF (20 ml)under N₂ flow. The mixture was stirred at −20° C. for 20 minutes, thencooled to −70° C. A solution of 6-bromo-2-chloro-3-phenylquinoline(0.0062 mol) in THF (40 ml) was added. The mixture was stirred at −70°C. for 1 hour. A solution of intermediate 21 (0.0094 mol) in THF (25 ml)was added. The mixture was stirred from −70° C. to room temperature for18 hours. H₂O and EtOAc were added. The organic layer was washed withsaturated NaCl, dried (MgSO₄), filtered, and the solvent was evaporated.The residue (4.3 g) was purified by column chromatography over silicagel (eluent: DCM/MeOH/NH₄OH 97/3/0.1; 10 μm). The pure fractions werecollected and the solvent was evaporated, yielding 0.77 g ofintermediate 24 (23%).

The following intermediates were prepared according to the methoddescribed above.

intermediate 32

intermediate 33

intermediate 34

c) Preparation of Intermediate 28

1.6M Butyllithium (0.029 mol) was added at −10° C. to a solution ofN-propyl-1-propanamine (0.029 mol) in THF (50 ml) under N₂ flow. Themixture was stirred for 20 minutes, then cooled to −70° C. A solution ofintermediate 2 (0.024 mol) in THF (30 ml) was added. The mixture wasstirred at −70° C. for 1 hour. A solution of3-(dimethylamino)-1-(2-thienyl)-1-propanone (0.029 mol) in THF (20 ml)was added. The mixture was stirred at −70° C. for 1 hour, then broughtto −20° C. and extracted with EtOAc. The organic layer was separated,dried (MgSO₄), filtered, and the solvent was evaporated. The residue waspurified by column chromatography over silica gel (eluent:DCM/MeOH/NH₄OH 96/4/0.1; 20-45 μm). The pure fractions were collectedand the solvent was evaporated. The residue (4.65 g) was crystallizedfrom DIPE. The precipitate was filtered off and dried, yielding 2.7 g ofintermediate 28 (M.P.: 168° C.). The mother layer was evaporated,yielding another 1.7 g of intermediate 28.

d) Preparation of Intermediate 25

1.6M Butyllithium (0.0112 mol) was added dropwise at −20° C. to asolution of N-(1-methylethyl)-2-propanamine (0.0112 mol) in THF (20 ml)under N₂ flow. The mixture was stirred at −20° C. for 30 minutes, thencooled to −70° C. A solution of intermediate 17 (0.0094 mol) in THF (20ml) was added. The mixture was stirred for 45 minutes. A solution ofintermediate 21 (0.0112 mol) in THF (10 ml) was added. The mixture wasstirred at −70° C. for 2 hours, poured out into H₂O at −30° C. andextracted with EtOAc. The organic layer was separated, dried (MgSO₄),filtered, and the solvent was evaporated. The residue (4 g) was purifiedby column chromatography over silica gel (eluent: DCM/MeOH 98/2; 15-40μm). The pure fractions were collected and the solvent was evaporated.The residue (3 g) was crystallized from DIPE. The precipitate wasfiltered off and dried, yielding 1.94 g of intermediate 25 (43%) (M.P.:140° C.).

e) Preparation of Intermediate 26

1.6M Butyllithium (0.013 mol) was added dropwise at −30° C. to a mixtureof N-(1-methylethyl)-2-propanamine (0.013 mol) in THF (20 ml) under N₂flow. The mixture stirred at −20° C. for 30 minutes, then cooled to −70°C. A solution of 2-chloro-4-methyl-3-phenylquinoline (0.011 mol) in THF(20 ml) was added. The mixture was stirred for 45 minutes. A solution ofintermediate 21 (0.013 mol) in THF (10 ml) was added. The mixture wasstirred at −70° C. for 2 hours, poured out into H₂O and extracted withEtOAc. The organic layer was separated, dried (MgSO₄), filtered, and thesolvent was evaporated. The residue (5 g) was purified by columnchromatography over silica gel (eluent: DCM/MeOH 98/2; 15-40 μm). Thepure fractions were collected and the solvent was evaporated, yielding 4g of intermediate 26 (78%).

f) Preparation of Intermediate 27

1.6M Butyllithium in hexane (0.0075 mol) was added dropwise at −70° C.to a mixture of intermediate 14 (0.0062 mol) in THF (20 ml) under N₂flow. The mixture was stirred at −70° C. for 1 hour. A solution ofintermediate 21 (0.0075 mol) in THF (10 ml) was added at −70° C. Themixture was stirred from −70° C. to room temperature then stirred for 18hours. H₂O was added. The mixture was extracted with EtOAc. The organiclayer was washed with saturated NaCl, dried (MgSO₄), filtered and thesolvent was evaporated. The residue (3 g) was purified by columnchromatography over silica gel (eluent: DCM/MeOH/NH₄OH 97/3/0.1; 15-40μm). The pure fractions were collected and the solvent was evaporated,yielding 1.1 g of intermediate 27 (39%).

The following intermediates were prepared according to the methoddescribed above.

intermediate 35

intermediate 36

intermediate 37

intermediate 38

intermediate 39

intermediate 40

B. Preparation of the Final Compounds Example B1 a) Preparation ofCompound 1

1.6M Butyllithium (0.0019 mol) was added dropwise at −70° C. to amixture of intermediate 8 (0.0016 mol) in THF (5 ml) under N₂ flow. Themixture was stirred at −70° C. for 1 hour. A solution of intermediate 21(0.0019 mol) in THF (2 ml) was added. H₂O was added. The mixture wasextracted with DCM. The organic layer was separated, dried (MgSO₄),filtered, and the solvent was evaporated The residue was purified bycolumn chromatography over silica gel (eluent: DCM/MeOH/NH₄OH 98/2/0.1;10 μm). The pure fractions were collected and the solvent wasevaporated, yielding 0.2 g of compound 1 (28%, MH+: 449).

The following final compounds were prepared according to the methoddescribed above.

compound 2 (MH+: 463)

compound 3 (MH+: 463)

compound 4 (M.P.: 173° C.)

compound 5 (MH+: 403)

compound 6 (MH+: 453)

b) Preparation of Compound 7

Butyllithium (0.0035 mol) was added dropwise at −20° C. to a solution ofN-(1-methylethyl)-2-propanamine (0.0034 mol) in THF (10 ml) under N₂flow. The mixture was stirred at −20° C. for 20 minutes, then cooled to−70° C. A solution of intermediate (0.0029 mol) in THF (10 ml) wasadded. The mixture was stirred at −70° C. for 2 hours. A solution ofintermediate 21 (0.0032 mol) in THF (10 ml) was added at −70° C. Themixture was stirred at −70° C. for 3 hours, poured out into ice waterand extracted with DCM. The organic layer was separated, dried (MgSO₄),filtered, and the solvent was evaporated. The residue (1.4 g) waspurified by column chromatography over silica gel (eluent:DCM/MeOH/NH₄OH 99/1/0.1; 15-40 μm). The desired fraction was collectedand the solvent was evaporated. The residue (0.968 g) was purified bycolumn chromatography over silica gel (eluent: DCM/MeOH/NH₄OH 98/2/0.2;15-40 μm). The pure fractions were collected and the solvent wasevaporated. The residue was dried, yielding 0.151 g of compound 7 (11%,oil, NMR confirms structure).

Example B2 a) Preparation of Compound 8

A 30% MeONa solution (2 ml) was added at room temperature to a mixtureof intermediate 23 (0.002 mol) in MeOH (2 ml). The mixture was stirredand refluxed overnight, poured out on ice and extracted with DCM. Theorganic layer was separated, dried (MgSO₄), filtered, and the solventwas evaporated. The residue (0.62 g) was purified by columnchromatography over silica gel (eluent: DCM/MeOH/NH₄OH 95/5/0.5; 15-40μm). The pure fractions were collected and the solvent was evaporated.The obtained residue (0.39 g) was crystallized from DIPE. Theprecipitate was filtered off and dried, yielding 0.15 g of compound 8(M.P.: 66° C.).

The following final compounds were prepared according to the methoddescribed above.

compound 9 (M.P.: 170° C.)

compound 10 (M.P.: 138° C.)

compound 11 (M.P.: 215° C.) as an ethanedioic acid salt (1:1)

compound 12 (M.P.: 160° C.) (was prepared as ethane dioic acid)

compound 13 (M.P.: 60° C.)

compound 14 (M.P.: 144° C.)

compound 150 (MH+: 403)

compound 16 (M.P.: 132° C.) as an ethanedioic acid salt (1:1)

b) Preparation of Compound 17

A mixture of intermediate 25 (0.0004 mol) and pyrrolidine (0.0021 mol)was stirred at 90° C. overnight, then poured out into H₂O and extractedwith DCM. The organic layer was separated, dried (MgSO₄), filtered, andthe solvent was evaporated. The residue (0.18 g) was purified by columnchromatography over silica gel (eluent: DCM/MeOH/NH₄OH 98/2/0.1; 10 μm).The desired fraction was collected and the solvent was evaporated,yielding 0.043 g of compound 17 (20%, MH+: 516).

The following final compounds were prepared according to the methoddescribed above.

compound 18 (MH+: 532)

compound 19 (M.P.: 195° C.)

compound 20 (MH+: 579)

c) Preparation of Compound 21

A mixture of intermediate 26 (0.0006 mol), phenyl boronic acid (0.0019mol), Pd(PPh₃)₄ (0.00006 mol) and Na₂CO₃ (0.0032 mol) in dimethyl ether(10 ml) was stirred at 90° C. overnight, poured out into H₂O andextracted with CH₂Cl₂. The organic layer was separated, dried (MgSO₄),filtered, and the solvent was evaporated. The residue (0.48 g) waspurified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH99/1; 10 μm). The pure fractions were collected and the solvent wasevaporated. Yield: 0.054 g of compound 21 (16%, M.P.: 173° C.).

d) Preparation of Compound 22

A mixture of intermediate 24 (0.0003 mol), imidazole (0.0018 mol) andK₂CO₃ (0.0011 mol) in acetonitrile (10 ml) was stirred and refluxed for48 hours, then cooled to room temperature. H₂O was added. The mixturewas extracted with EtOAc. The organic layer was washed with saturatedaqueous NaCl solution, dried (MgSO₄), filtered, and the solvent wasevaporated. The residue (0.23 g) was purified by column chromatographyover silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.1). The purefractions were collected and the solvent was evaporated. Yield: 0.09 gof compound 22 (42%) (melting point: 136° C.).

The following final compounds were prepared according to the methoddescribed above.

compound 23 (MH+: 743)

compound 24 (M.P.: 200° C.)

compound 25 (MH+: 699)

compound 26 (MH+: 725)

compound 27 (MH+: 624)

compound 28 (MH+: 656)

compound 29 (MH+: 610)

compound 30 (MH+: 594)

compound 31 (MH+: 703)

compound 32 (MH+: 649)

compound 33 (M.P.: 167° C.)

compound 34 (MH+: 568)

compound 35 (MH+: 544)

compound 36 (MH+: 693)

compound 37 (MH+: 573)

compound 38 (MH+: 698)

compound 39 (MH+: 518)

compound 40 (MH+: 775)

compound 41 (M.P.: 217° C.)

e) Preparation of Compound 42

A mixture of intermediate 27 (0.0005 mol),3-(1,3,2-dioxaborinan-2-yl)pyridine (0.0008 mol),tetrakis(triphenylphosphine)palladium (0.0005 mol) and a 2M K₂CO₃solution (0.0027 mol) in dimethyl ether (7 ml) and MeOH (3 ml) wasstirred at 100° C. for 18 hours under N₂ flow, then cooled to roomtemperature. H₂O was added. The mixture was extracted with EtOAc. Theorganic layer was washed with saturated aqueous NaCl solution, dried(MgSO₄), filtered, and the solvent was evaporated. The residue (0.34 g)was taken up in 2-propanone (6 ml). Oxalic acid was added. The mixturewas stirred. The precipitate was filtered off and dried at 60° C. undera vacuo, yielding 0.29 g of compound 42 as an ethanedioic acid salt(1:2) (80%, M.P.: 151° C.).

The following final compounds were prepared according to the methoddescribed above.

compound 43 (MH+: 460)

compound 44 (MH+: 450)

f) Preparation of Compound 45

ethanedioic acid (1:2.5)

A mixture of intermediate 37 (0.0007 mol) in N-methylmethanamine (10 ml)and acetonitrile (10 ml) was stirred at 90° C. for 12 hours, poured outinto H₂O/K₂CO₃ and extracted with DCM. The organic layer was separated,dried (MgSO₄), filtered, and the solvent was evaporated. The obtainedfraction (0.25 g) was stirred at 90° C. for 72 hours and purified bycolumn chromatography over kromasil (eluent: DCM/MeOH 99/1; 10 μm). Thedesired product fraction was collected and the solvent was evaporated.The residue (0.08 g) was dissolved in oxalic acid/2-propanol andconverted into the ethanedioic acid salt (1:2.5). The precipitate wasfiltered off and dried, yielding 0.07 g of compound 45 (14%, M.P.: 136°C.).

The following final compounds were prepared according to the methoddescribed above.

compound 46 (MH+: 524)

compound 47 (MH+: 426)

g) Preparation of Compound 48

A mixture of KOH (0.0011 mol) in 1-piperidineethanol (2 ml) was stirredat 80° C. till KOH disappeared. Intermediate 23 (0.0009 mol) was added.The mixture was stirred at 80° C. overnight, poured out on ice andextracted with DCM. The organic layer was separated, dried (MgSO₄),filtered, and the solvent was evaporated. The residue (2.49 g) wascrystallized from DIPE. The precipitate was filtered off and dried,yielding 0.308 g of compound 48 (M.P.: 131° C.).

The following final compound was prepared according to the methoddescribed above.

compound 49 (M.P.: 141° C.)

h) Preparation of Compound 50

A mixture of intermediate 23 (0.000137 mol), N-methylmethanamine(0.000412 mol, 3 equiv.) and K₂CO₃ (3 equiv.) in acetonitrile (2 ml) wasstirred at 80° C. for 12 hours, poured out into H₂O and extracted withDCM. The organic layer was separated, dried (MgSO₄), filtered, and thesolvent was evaporated. The obtained fraction was purified by columnchromatography over silica gel, then the desired product fraction wascollected and the solvent was evaporated, yielding 0.07 g of compound 50(54.79%, MH+: 518).

The following final compounds were prepared according to the methoddescribed above.

compound 51 (MH+: 649)

compound 52 (MH+: 544)

compound 53 (MH+: 556)

compound 54 (MH+: 677)

compound 55 (MH+: 608)

compound 56 (MH+ 648)

compound 57 (MH+: 636)

compound 58 (MH+: 617)

compound 59 (MH+: 684)

compound 60 (MH+: 562)

compound 61 (MH+: 572)

compound 62 (MH+: 615)

compound 63 (MH+: 601)

Example B3 a) Preparation of Compound 64

A mixture of compound 9 (0.0003 mol),3-(1,3,2-dioxaborinan-2-yl)pyridine (0.0006 mol),tetrakis(triphenylphosphine)palladium (0.00003 mol) and a 2M K₂CO₃solution (0.0015 mol) in dimethyl ether (6 ml) and MeOH (2 ml) wasstirred at 100° C. for 18 hours under N₂ flow, then cooled to roomtemperature. H₂O was added. The mixture was extracted with EtOAc. Theorganic layer was washed with saturated NaCl, dried (MgSO₄), filtered,and the solvent was evaporated. The residue (0.14 g) was taken up in2-propanone (2 ml). Oxalic acid (2 equivalents) was added. The mixturewas stirred for 10 minutes. The precipitate was filtered, washed with2-propanone and dried at 70° C. under a vacuo, yielding 0.077 g ofcompound 64 as ethanedioic acid salt (1:1.5) (38%, M.P.: 156° C.).

The following final compound was prepared according to the methoddescribed above.

compound 65 (M.P.: 177° C.)

b) Preparation of Compound 66

A mixture of compound 8 (0.0003 mol),tetrakis(triphenylphosphine)-palladium (0.00003 mol), a 2M Na₂CO₃solution (0.0019 mol) and 3-(1,3,2-dioxaborinan-2-yl)pyridine (0.0011mol) in dimethyl ether (6 ml) was stirred at 100° C. overnight, thenpoured out into H₂O and extracted with DCM. The organic layer wasseparated, dried (MgSO₄), filtered, and the solvent was evaporated. Theresidue was purified by column chromatography over kromasil (eluent:toluene/2-propanol/NH₄OH 80/20/1; 10 μm). The pure fractions werecollected and the solvent was evaporated. The residue (0.1 g, 51%) wascrystallized from DIPE/acetonitrile. The precipitate was filtered offand dried, yielding 0.057 g of compound 66 (M.P.: 180° C.).

The following final compound was prepared according to the methoddescribed above.

compound 67 (M.P.: 199° C.)

c) Preparation of Compound 68

A mixture of compound 10 (0.0007 mol),tetrakis(triphenylphosphine)-palladium (0.00007 mol) andtetramethylstannane (0.0016 mol) in toluene (6 ml) was stirred andrefluxed overnight. H₂O was added. The mixture was extracted with DCM.The organic layer was separated, dried (MgSO₄), filtered, and thesolvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: DCM/MeOH/NH₄OH 95/5/0.3; 20 μm).The pure fractions were collected and the solvent was evaporated,yielding 0.038 g of compound 68 (11%, MH+: 447).

Example B4 Preparation of Compound 69

A mixture of intermediate 32 (0.0016 mol) in 6N HCl (5 ml) and THF (10ml) was stirred at 80° C. for 48 hours, then cooled to room temperature,poured out into a 10% K₂CO₃ solution and extracted with EtOAc. Theorganic layer was washed with saturated NaCl, dried (MgSO₄), filteredand the solvent was evaporated. The residue was crystallized fromdiethyl ether/2-propanone. The precipitate was filtered off and dried.Part of this fraction (0.3 g of 0.6 g (44%)) was taken up in hot2-propanone. The precipitate was filtered off and dried, yielding 0.2 gof compound 69 (15%, M.P.: 190° C.).

Example B5 a) Preparation of Compound 70

n-Butyl lithium (0.0022 mol) was added slowly at −20° C. to a mixture ofdiisopropyl amine (0.0022 mol) in THF (10 ml) under N₂. The mixture wasstirred for 20 minutes and then cooled to −70° C. A solution ofintermediate 17a (0.0019 mol) in THF (10 ml) was added. The mixture wasstirred for 1 hour. A solution of3-(dimethylamino)-1-(1-naphthalenyl)-1-propanone, (0.0028 mol) in THF(10 ml) was added at −70° C. The mixture was stirred for 1 hour. H₂O wasadded. The mixture was extracted with EtOAc. The organic layer wasseparated, dried over magnesium sulfate, filtered and the solvent wasevaporated. The residue (1.13 g) was purified by column chromatographyover silica gel (eluent: CH₂Cl₂/iPrOH/NH₄OH 96/4/0.2; 15-40 μm). Thepure fractions were collected and the solvent was evaporated. Yield:0.04 g of compound 70 (4%; MH+: 491).

b) Preparation of Compound 71

This compound has been prepared according to B5a).

The residue (1 g) was purified by column chromatography over silica gel(eluent: CH₂Cl₂/MeOH/NH₄OH 99/1/0.1; 15-40 μm). The pure fractions werecollected and the solvent was evaporated. The residue (0.32 g, 37%) wascrystallized from diisopropylether. The precipitate was filtered off anddried. Yield: 0.133 g of compound 71 (15%, melting point: 123° C.).

C. Analytical Methods

The mass of the compounds was recorded with LCMS (liquid chromatographymass spectrometry). Three methods were used which are described below.The data are gathered in Table 1 below.

LCMS—Method 1

LCMS analysis was carried out (electrospray ionization in positive mode,scanning mode from 100 to 900 amu) on a Kromasil C18 column (Interchim,Montluçon, FR; 5 μm, 4.6×150 mm) with a flow rate of 1 ml/minute. Twomobile phases (mobile phase A: 30% 6.5 mM ammonium acetate+40%acetonitrile+30% formic acid (2 ml/l); mobile phase B: 100%acetonitrile) were employed to run a gradient condition from 100% A for1 minute to 100% B in 4 minutes, 100% B for 5 minutes to 100% A in 3minutes, and reequilibrate with 100% A for 2 minutes.

LCMS—Method 2

LCMS analysis was carried out (electrospray ionization in both positiveand negative (pulsed) mode scanning from 100 to 1000 amu) on a KromasilC18 column (Interchim, Montluçon, FR; 3.5 μm, 4.6×100 mm) with a flowrate of 0.8 ml/minute. Two mobile phases (mobile phase A: 35% 6.5 mMammonium acetate+30% acetonitrile+35% formic acid (2 ml/l); mobile phaseB: 100% acetonitrile) were employed to run a gradient condition from100% A for 1 minute to 100% B in 4 minutes, 100% B at a flow rate of 1.2ml/minute for 4 minutes to 100% A at 0.8 ml/minute in 3 minutes, andreequilibrate with 100% A for 1.5 minute.

LCMS—Method 3

LCMS analysis was carried out (electrospray ionization in positive mode,scanning from 100 to 900 amu) on a Xterra MS C18 column (Waters,Milford, Mass.; 5 μm, 4.6×150 mm) with a flow rate of 1 ml/minute. Twomobile phases (mobile phase A: 85% 6.5 mM ammonium acetate+15%acetonitrile; mobile phase B: 20% 6.5 mM ammonium acetate+80%acetonitrile) were employed to run a gradient condition from 100% A for3 minutes to 100% B in 5 minutes, 100% B at a flow rate of 1.2 ml/minutefor 6 minutes to 100% A at 0.8 ml/minute in 3 minutes, and reequilibratewith 100% A for 3 minutes.

TABLE 1 Analytical method used Compound LC/GC/MS No Method 1 1 68 2 2 13 1 5 1 6 1 15 1 17 3 18 1 20 1 23 2 25 2 26 2 27 2 28 2 29 2 30 2 31 232 1 34 2 35 1 36 1 37 1 38 2 39 1 40 2 43 3 44 3 46 1 47 3 50 1 51 1 521 53 1 54 1 55 1 56 1 57 1 58 1 59 1 60 1 61 1 62 1 63 1 70 1

Pharmacological Examples Preparation of Bacterial Suspensions forSusceptibility Testing

The bacteria used in this study were grown overnight in flaskscontaining 100 ml Mueller-Hinton Broth (Becton Dickinson—cat. no.275730) in sterile de-ionized water, with shaking, at 37° C. Stocks (0.5ml/tube) were stored at −70° C. until use. Bacteria titrations wereperformed in microtiter plates and colony forming units (CFUs) weredetermined. In general, an inoculum level of approximately 100 CFUs wasused for susceptibility testing.

Anti Bacterial Susceptibility Testing: IC₉₀ Determination

Microtitre Plate Assay

Flat-bottom, sterile 96-well plastic microtiter plates were filled with180 μl of sterile deionized water, supplemented with 0.25% BSA.Subsequently, stock solutions (7.8×final test concentration) ofcompounds were added in 45 μl volumes in column 2 Serial five-folddilutions (45 μl in 180 μl) were made directly in the microtiter platesfrom column 2 to reach column 11. Untreated control samples with(column 1) and without (column 12) inoculum were included in eachmicrotiter plate. Depending on the bacteria type, approximately 10 to 60CFU per well of bacteria inoculum (100 TCID50), in a volume of 100 μl in2.8× Mueller-Hinton broth medium, was added to the rows A to H, exceptcolumn 12. The same volume of broth medium without inoculum was added tocolumn 12 in row A to H. The cultures were incubated at 37° C. for 24hours under a normal atmosphere (incubator with open air valve andcontinuous ventilation). At the end of incubation, one day afterinoculation, the bacterial growth was quantitated fluorometrically.Therefore resazurin (0.6 mg/ml) was added in a volume of 20 μl to allwells 3 hours after inoculation, and the plates were re-incubatedovernight. A change in colour from blue to pink indicated the growth ofbacteria.

The fluorescence was read in a computer-controlled fluorometer(Cytofluor Biosearch) at an excitation wavelength of 530 nm and anemission wavelength of 590 nm. The % growth inhibition achieved by thecompounds was calculated according to standard methods. The IC₉₀(expressed in μg/ml) was defined as the 90% inhibitory concentration forbacterial growth. The results are shown in Table 2.

Agar Dilution Method.

MIC₉₉ values (the minimal concentration for obtaining 99% inhibition ofbacterial growth) can be determined by performing the standard Agardilution method according to NCCLS standards* wherein the media usedincludes Mueller-Hinton agar. * Clinical laboratory standard institute.2005. Methods for dilution Antimicrobial susceptibility tests forbacteria that grows Aerobically: approved standard—sixth edition

Time Kill Assays

Bactericidal or bacteriostatic activity of the compounds may bedetermined in a time kill assay using the broth microdilution method *.In a time kill assay on Staphylococcus aureus and methicillin resistantS. aureus (MRSA), the starting inoculum of S. aurues and MRSA is 10⁶CFU/ml in Muller Hinton broth. The antibacterial compounds are used atthe concentration of 0.1 to 10 times the MIC (i.e. IC₉₀ as determined inmicrotitre plate assay). Wells receiving no antibacterial agentconstitute the culture growth control. The plates containing themicroorganism and the test compounds are incubated at 37° C. After 0, 4,24, and 48 hrs of incubation samples are removed for determination ofviable counts by serial dilution (10⁻¹ to 10⁻⁶) in sterile PBS andplating (200 μl) on Mueller Hinton agar. The plates are incubated at 37°C. for 24 hrs and the number of colonies are determined Killing curvescan be constructed by plotting the log₁₀CFU per ml versus time. Abactericidal effect is commonly defined as 3-log₁₀ decrease in number ofCFU per ml as compared to untreated inoculum. The potential carryovereffect of the drugs is removed by serial dilutions and counting thecolonies at highest dilution used for plating. No carryover effect isobserved at the dilution of 10⁻² used for plating. This results in limitof detection 5×10² CFU/ml or <2.7 log CFU/ml. * Zurenko, G. E. et al. Invitro activities of U-100592 and U-100766, novel oxazolidinoneantibacterial agents. Antimicrob. Agents Chemother. 40, 839-845 (1996).

Determination of Cellular ATP Levels

In order to analyse the change in the total cellular ATP concentration(using ATP bioluminescence Kit, Roche), assays are carried out bygrowing a culture of S. aureus (ATCC29213) stock in 100 ml MuellerHinton flasks and incubate in a shaker-incubator for 24 hrs at 37° C.(300 rpm). Measure OD₄₀₅ nm and calculate the CFU/ml. Dilute thecultures to 1×10⁶ CFU/ml (final concentration for ATP measurement: 1×10⁵CFU/100 μl per well) and add test compound at 0.1 to 10 times the MIC(i.e. IC₉₀ as determined in microtitre plate assay). Incubate thesetubes for 0, 30 and 60 minutes at 300 rpm and 37° C. Use 0.6 mlbacterial suspension from the snap-cap tubes and add to a new 2 mleppendorf tubes. Add 0.6 ml cell lysis reagent (Roche kit), vortex atmax speed and incubate for 5 minutes at room temperature. Cool on ice.Let the luminometer warm up to 30° C. (Luminoskan Ascent Labsystems withinjector). Fill one column (=6 wells) with 100 μl of the same sample.Add 100 μl Luciferase reagent to each well by using the injector system.Measure the luminescence for 1 sec.

TABLE 2 IC₉₀ values (μg/ml) determined according to the Microtitre plateassay. IC90 (μg/ml) Comp STA SPN SPY SMU EFA LMO BSU ECO PAE STA STA STAEFA ECO ECO No. 29213 6305 8668 33402 29212 49594 43639 35218 27853RMETHIC 25923 43300 14506 1403 25922 64 8.3 10.5 2.1 2.1 13.2 13.2 8.313.2 11.8 6.6 10.5 8 10.1 11.3 10.1 10.1 40.2 12.7 12.7 11.3 11.3 11.346 10.5 10.5 10.5 10.5 10.5 10.5 10.5 10.5 9.3 11.7 10.5 10.5 12 10.812.1 10.8 10.8 13.6 13.6 13.6 10.8 12.1 12.1 10.8 10.8 10 12.9 11.5 10.210.2 10.2 10.2 12.9 10.2 11.5 12.9 24 11.8 14.9 11.8 11.8 14.9 14.9 11.814.9 14.9 13.2 11.8 9 10.5 13.3 10.5 10.5 10.5 10.5 10.5 11.8 11.8 13.311.8 13 12.1 10.8 12.1 12.1 12.1 12.1 12.1 12.1 12.1 22 14.2 12.6 11.211.2 14.2 14.2 14.2 14.2 12.6 33 14.5 14.5 11.5 11.5 14.5 14.5 11.5 14.514.5 14.5 46.0 20 11.6 14.6 11.6 14.6 14.6 14.6 14.6 11.6 14.6 46.0 13.013.0 14.6 65 13.5 13.5 13.5 13.5 13.5 13.5 13.5 13.5 13.5 13.5 19 14.514.5 11.5 11.5 14.5 14.5 14.5 14.5 14.5 12.9 11.5 59 15.3 17.2 15.3 15.317.2 10.9 10.9 15.3 17.2 54.4 54.4 17.2 54.4 54 17.0 17.0 17.0 17.0 17.017.0 26 16.3 3.6 2.9 2.9 3.6 3.6 14.5 2.9 18.2 7.3 14.5 66 40.0 50.440.0 40.0 50.4 50.4 50.4 40.0 50.4 50.4 67 51.0 22.8 51.0 51.0 51.0 51.051.0 51.0 51.0 49 44.7 56.3 22.4 44.7 56.3 56.3 56.3 56.3 56.3 56.3 56.348 53.7 60.3 47.9 47.9 60.3 60.3 60.3 47.9 60.3 53.7 70 12.3 12.3 9.89.8 49.1 39.0 12.3 9.8 12.3 12.3 71 11.5 11.5 9.2 9.2 11.5 9.2 11.5 11.511.5 11.5 21 12.8 12.8 12.8 12.8 12.8 12.8 12.8 12.8 12.8 6 9.0 11.4 9.09.0 11.4 11.4 11.4 9.0 10.1 11.4 9.0 45 9.2 11.6 9.2 9.2 11.6 11.6 9.211.6 46.2 10.3 10.3 2 9.2 11.6 9.2 9.2 11.6 11.6 9.2 9.2 11.6 11.6 9.28.2 5 10.1 10.1 10.1 10.1 10.1 10.1 10.1 9.0 10.1 4 10.4 10.4 10.4 10.410.4 10.4 10.4 10.4 10.4 1 11.3 11.3 9.0 9.0 11.3 11.3 11.3 11.3 11.311.3 11.3 3 11.6 5.2 9.2 9.2 11.6 11.6 11.6 9.2 11.6 11.6 9.2 7 9.5 12.012.0 10.7 7.6 37.9 10.7 37.9 7.6 11 11.3 11.3 9.0 11.3 11.3 11.3 11.311.3 11.3 14 10.4 10.4 10.4 10.4 10.4 10.4 10.4 10.4 10.4 15 10.1 10.110.1 10.1 10.1 10.1 10.1 10.1 10.1 16 10.4 10.4 10.4 10.4 10.4 10.4 10.410.4 10.4 42 39.4 12.5 12.5 12.5 39.4 12.5 12.5 49.6 9.9 43 11.5 11.511.5 11.5 11.5 44 11.3 11.3 11.3 11.3 11.3 11.3 11.3 11.3 11.3 47 10.710.7 10.7 10.7 10.7 10.7 10.7 10.7 10.7 69 13.3 13.3 13.3 13.3 41.9 52.813.3 52.8 52.8 BSU 43639 means Bacillus subtilis (ATCC43639); ECO 25922means Escherichia coli (ATCC25922); ECO 35218 means Escherichia coli(ATCC35218); ECO 1403 means Escherichia coli (ATCC1403); EFA 14506 meansEnterococcus faecalis (ATCC14506); EFA 29212 means Enterococcus faecalis(ATCC29212); LMO 49594 means Listeria monocytogenes (ATCC49594); PAE27853 means Pseudomonas aeruginosa (ATCC27853); SMU 33402 meansStreptococcus mutans (ATCC33402); SPN 6305 means Streptococcuspneumoniae (ATCC6305); SPY 8668 means Streptococcus pyogens (ATCC8668);STA 43300 means Staphylococcus aureus (ATCC43300); STA 25923 meansStaphylococcus aureus (ATCC25923); STA 29213 means Staphylococcus aureus(ATCC29213); STA RMETH means methicilline resistant Staphylococcusaureus (MRSA) (a clinical isolate from the University of Antwerp). ATCCmeans American type tissue culture.

1. A method for treating a non-mycobacterial bacterial infection in amammal, wherein said non-mycobacterial bacterial infection is aninfection with Staphylococci, Enterococci or Streptococci, said methodcomprising administering an effective amount of a compound of Formula(Ia) or (Ib) to said mammal:

a pharmaceutically acceptable acid or base addition salt thereof or astereochemically isomeric form thereof, wherein R¹ is hydrogen, halo,haloalkyl, cyano, hydroxy, Ar, Het, alkyl, alkyloxy, alkylthio,alkyloxyalkyl, alkylthioalkyl, Ar-alkyl or di(Ar)alkyl; p is an integerequal to 1, 2 or 3; R² is hydrogen; alkyl; hydroxy; mercapto; alkyloxyoptionally substituted with amino or mono or di(alkyl)amino or a radicalof formula

wherein Z is CH₂, CH—R¹⁰, O, S, N—R¹⁰ and t is an integer equal to 1 or2 and the dotted line represents an optional bond; alkyloxyalkyloxy;alkylthio; mono or di(alkyl)amino wherein alkyl may optionally besubstituted with one or two substituents each independently be selectedfrom alkyloxy or Ar or Het or morpholinyl or 2-oxopyrrolidinyl; Ar; Hetor a radical of formula

wherein Z is CH₂, CH—R¹⁰, O, S, N—R¹⁰; t is an integer equal to 1 or 2;and the dotted line represents an optional bond; R³ is alkyl, Ar,Ar-alkyl, Het or Het-alkyl; q is an integer equal to zero, 1, 2, 3 or 4;X is a direct bond or CH₂; R⁴ and R⁵ each independently are hydrogen,alkyl or benzyl; or R⁴ and R⁵ together and including the N to which theyare attached may form a radical selected from the group of pyrrolidinyl,2-pyrrolinyl, 3-pyrrolinyl, pyrrolyl, pyrazolidinyl, 2-imidazolinyl,2-pyrazolinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl,piperazinyl, imidazolidinyl, pyridazinyl, pyrimidinyl, pyrazinyl,triazinyl, morpholinyl and thiomorpholinyl, each of said ringsoptionally being substituted with alkyl, halo, haloalkyl, hydroxy,alkyloxy, amino, mono- or dialkylamino, alkylthio, alkyloxyalkyl,alkylthioalkyl or pyrimidinyl; R⁶ is hydrogen or a radical of formula

wherein s is an integer equal to zero, 1, 2, 3 or 4; r is an integerequal to 1, 2, 3, 4 or 5; and R¹¹ s hydrogen, halo, haloalkyl, hydroxy,Ar, alkyl, alkyloxy, alkylthio, alkyloxyalkyl, alkylthioalkyl, Ar-alkylor di(Ar)alkyl; or two vicinal R¹¹ radicals may be taken together toform together with the phenyl ring to which they are attached anaphthyl; R⁷ is absent, hydrogen, alkyl, Ar or Het; R⁸ is hydrogen oralkyl; R⁹ is oxo; or R⁸ and R⁹ together form the radical —CH═CH—N═; R¹⁰is hydrogen, alkyl, hydroxyl, aminocarbonyl, mono- ordi(alkyl)aminocarbonyl, Ar, Het, alkyl substituted with one or two Het,alkyl substituted with one or two Ar, Het-C(═O)—, Ar—C(═O)—; alkyl is astraight or branched saturated hydrocarbon radical having from 1 to 6carbon atoms; or is a cyclic saturated hydrocarbon radical having from 3to 6 carbon atoms; or is a cyclic saturated hydrocarbon radical havingfrom 3 to 6 carbon atoms attached to a straight or branched saturatedhydrocarbon radical having from 1 to 6 carbon atoms; wherein each carbonatom can be optionally substituted with hydroxy, alkyloxy or oxo; Ar isa homocycle selected from the group of phenyl, naphthyl, acenaphthyl,tetrahydronaphthyl, each optionally substituted with 1, 2 or 3substituents, each substituent independently selected from the group ofhydroxy, halo, cyano, nitro, amino, mono- or dialkylamino, alkyl,haloalkyl, alkyloxy, haloalkyloxy, carboxyl, alkyloxycarbonyl,alkylcarbonyl, aminocarbonyl, morpholinyl and mono- ordialkylaminocarbonyl; Het is a monocyclic heterocycle selected from thegroup of N-phenoxypiperidinyl, piperidinyl, pyrrolyl, pyrazolyl,imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl andpyridazinyl; or a bicyclic heterocycle selected from the group ofquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl,benzothienyl, 2,3-dihydrobenzo[1,4]dioxinyl or benzo[1,3]dioxolyl; eachmonocyclic and bicyclic heterocycle may optionally be substituted on acarbon atom with 1, 2 or 3 substituents, each substituent independentlyselected from the group of halo, hydroxy, alkyl or alkyloxy; halo is asubstituent selected from the group of fluoro, chloro, bromo and iodoand haloalkyl is a straight or branched saturated hydrocarbon radicalhaving from 1 to 6 carbon atoms or a cyclic saturated hydrocarbonradical having from 3 to 6 carbon atoms or a cyclic saturatedhydrocarbon radical having from 3 to 6 carbon atoms attached to astraight or branched saturated hydrocarbon radical having from 1 to 6carbon atoms; wherein one or more carbon atoms are substituted with oneor more halo atoms; provided that when R⁷ is absent then the

radical may be placed in position 4 of the quinoline ring.
 2. A methodaccording to claim 1 wherein R¹ is hydrogen, halo or Het.
 3. A methodaccording to claim 2 wherein R¹ is halo.
 4. A method according to claim1 wherein p is equal to
 1. 5. A method according to claim 1 wherein R²is alkyloxy; Het; Ar; mono or di(alkyl)amino wherein alkyl mayoptionally be substituted with one or two Ar substituents; a radical offormula

wherein Z is N—R¹⁰; t is an integer equal to 2; alkyloxy substitutedwith amino or mono or di(alkyl)amino or a radical of formula

wherein Z is CH₂ and t is an integer equal to
 2. 6. A method accordingto claim 5 wherein R² is alkyloxy.
 7. A method according to claim 1wherein R³ is naphthyl, phenyl or Het, each optionally substituted with1 or 2 substituents.
 8. A method according to claim 7 wherein R³ isnaphthyl, phenyl, 3,5-dihalophenyl, thienyl, furanyl or benzofuranyl. 9.A method according to claim 1 wherein q is equal to
 1. 10. A methodaccording to claim 1 wherein R⁴ and R⁵ each independently are alkyl. 11.A method according to claim 1 wherein R⁶ is benzyl or phenyl.
 12. Amethod according to claim 1 wherein R⁷ is hydrogen.
 13. A methodaccording to claim 1 wherein X is a direct bond.
 14. A method accordingto claim 1 wherein X is CH₂.
 15. A method according to claim 1 whereinthe compound is a compound according to Formula (Ia).
 16. A methodaccording to claim 1 wherein the bacterial infection is an infectionwith a gram-positive bacterium.
 17. The method according to claim 1wherein the bacterial infection is an infection with methicillinresistant Staphylococcus aureus (MRSA), methicillin resistant coagulasenegative staphylococci (MRCNS), penicillin resistant Streptococcuspneumoniae or multiple resistant Enterococcus faecium.
 18. The methodaccording to claim 1 wherein the bacterial infection is an infectionwith Staphylococcus aureus or Streptococcus pneumoniae.
 19. The methodaccording to claim 1 wherein the bacterial infection is an infectionwith methicillin resistant Staphylococcus aureus (MRSA).